Measuring patient centeredness with German language Patient-Reported Experience Measures (PREM)-A systematic review and qualitative analysis according to COSMIN.

BACKGROUND: Patient centeredness is an integral part of the quality of care. Patient-reported experience measures (PREMs) are assumed to be an appropriate tool to assess patient-centredness. An evaluation of German-speaking PREMs is lacking. OBJECTIVE: To perform a systematic review and qualitative analysis of psychometric measurement qualities of German-language PREMs using for the first time a comprehensive framework of patient centredness. METHODS: A systematic literature search was performed in Medline, PsycInfo, CINHAL, Embase, Cochrane database (last search 9th November 2021) for studies describing generic, surgery- or cancer care-specific PREMs. All questionnaires that were developed in or translated into German were included. The content of the included PREMs was evaluated using a comprehensive framework of patient centredness covering 16 domains. Baseline data of all PREM studies were extracted by two independent reviewers. Psychometric measurement qualities of the PREMs were assessed using current COSMIN guidelines. RESULTS: After removal of duplicates 3,457 abstracts were screened, of which 3,345 were excluded. The remaining 112 articles contained 51 PREMs, of which 12 were either developed in (4 PREMs) or translated into German (8 PREMs). Eight PREMs were generic (NORPEQ, PPE-15, PEACS, HCAHPS, QPPS, DUQUE, PEQ-G, Schoenfelder et al.), 4 cancer care-specific (EORTC IN-PATSAT32, PSCC-G, Danish National Cancer Questionnaire, SCCC) and none was surgery-specific. None of the PREMs covered all domains of patient-centeredness. Overall rating of structural validity was adequate only for PEACS and HCAHPS. High ratings for internal consistency were given for NORPEQ, Schoenfelder et al., PSCC-G and the SCCC. Cross-cultural validity for translated questionnaires was adequate only for the PSCC-G, while reliability was adequately assessed only for the EORTC IN-PATSAT32. Due to a lack of measurement gold standard and minimal important change, criterion validity and measurement invariance could not be assessed for any of the PREMs. CONCLUSION: This is the first systematic review using a comprehensive framework of patient centredness and shows that none of the included PREMs, even those translated from other languages into German, cover all aspects of patient centredness. Furthermore, all included PREMS show deficits in the results or evaluation of psychometric measurement properties. Nonetheless, based on the results, the EORTC IN-PATSAT32 and PSCC-G can be recommended for use in cancer patients in the German-language region, while the German versions of the HCAHPS, NORPEQ, PPE-15 and PEACS can be recommended as generic PREMs. TRIAL REGISTRATION: Registration. PROSPERO CRD42021276827.

Malnutrition outweighs the effect of the obesity paradox.

BACKGROUND: High body mass index (BMI) is paradoxically associated with better outcome in patients with heart failure (HF). The effects of malnutrition on this phenomenon across the whole spectrum of HF have not yet been studied. METHODS: In this observational study, patients were classified by guideline diagnostic criteria to one of three heart failure subtypes: reduced (HFrEF), mildy reduced (HFmrEF), and preserved ejection fraction (HFpEF). Data were retrieved from the Viennese-community healthcare provider network between 2010 and 2020. The relationship between BMI, nutritional status reflected by the prognostic nutritional index (PNI), and survival was assessed. Patients were classified by the presence (PNI < 45) or absence (PNI ≥ 45) of malnutrition. RESULTS: Of the 11 995 patients enrolled, 6916 (58%) were classified as HFpEF, 2809 (23%) HFmrEF, and 2270 HFrEF (19%). Median age was 70 years (IQR 61-77), and 67% of patients were men. During a median follow-up time of 44 months (IQR 19-76), 3718 (31%) of patients died. After adjustment for potential confounders, BMI per IQR increase was independently associated with better survival (adj. hazard ratio [HR]: 0.91 [CI 0.86-0.97], P = 0.005), this association remained significant after additional adjustment for HF type (adj. HR: 0.92 [CI 0.86-0.98], P = 0.011). PNI was available in 10 005 patients and lowest in HFrEF patients. PNI was independently associated with improved survival (adj. HR: 0.96 [CI 0.95-0.97], P < 0.001); additional adjustment for HF type yielded similar results (adj. HR: 0.96 [CI 0.96-0.97], P < 0.001). Although obese patients experienced a 30% risk reduction, malnutrition at least doubled the risk for death with 1.8- to 2.5-fold higher hazards for patients with poor nutritional status compared with normal weight well-nourished patients. CONCLUSIONS: The obesity paradox seems to be an inherent characteristic of HF regardless of phenotype and nutritional status. Yet malnutrition significantly changes trajectory of outcome with regard to BMI alone: obese patients with malnutrition have a considerably worse outcome compared with their well-nourished counterparts, outweighing protective effects of high BMI alone. In this context, routine recommendation towards weight loss in patients with obesity and HF should generally be made with caution and focus should be shifted on nutritional status.

Inflammation-Based Scores as a Common Tool for Prognostic Assessment in Heart Failure or Cancer.

Background: Inflammation-based scores are widely tested in cancer and have been evaluated in cardiovascular diseases including heart failure. Objectives: We investigated the impact of established inflammation-based scores on disease severity and survival in patients with stable heart failure with reduced ejection fraction (HFrEF) paralleling results to an intra-institutional cohort of treatment naïve cancer patients. Methods: HFrEF and cancer patients were prospectively enrolled. The neutrophil-to-lymphocyte-ratio (NLR), the monocyte-to-lymphocyte-ratio (MLR), the platelet-to-lymphocyte-ratio (PLR), and the prognostic nutritional index (PNI) at index day were calculated. Association of scores with disease severity and impact on overall survival was determined. Interaction analysis was performed for the different populations. Results: Between 2011 and 2017, a total of 818 patients (443 HFrEF and 375 cancer patients) were enrolled. In HFrEF, there was a strong association between all scores and disease severity reflected by NT-proBNP and NYHA class (p ≤ 0.001 for all). In oncologic patients, association with tumor stage was significant for the PNI only (p = 0.035). In both disease entities, all scores were associated with all-cause mortality (p ≤ 0.014 for all scores). Kaplan-Meier analysis confirmed the discriminatory power of all scores in the HFrEF and the oncologic study population, respectively (log-rank p ≤ 0.026 for all scores). A significant interaction with disease (HFrEF vs. cancer) was observed for PNI (p interaction = 0.013) or PLR (p interaction = 0.005), respectively, with higher increase in risk per inflammatory score increment for HFrEF. Conclusion: In crude models, the inflammatory scores NLR, MLR, PLR, and PNI are associated with severity of disease in HFrEF and with survival in HFrEF similarly to cancer patients. For PNI and PLR, the association with increase in risk per increment was even stronger in HFrEF than in malignant disease.

Relevance of Neutrophil Neprilysin in Heart Failure.

Significant expression of neprilysin (NEP) is found on neutrophils, which present the transmembrane integer form of the enzyme. This study aimed to investigate the relationship of neutrophil transmembrane neprilysin (mNEP) with disease severity, adverse remodeling, and outcome in HFrEF. In total, 228 HFrEF, 30 HFpEF patients, and 43 controls were enrolled. Neutrophil mNEP was measured by flow-cytometry. NEP activity in plasma and blood cells was determined for a subset of HFrEF patients using mass-spectrometry. Heart failure (HF) was characterized by reduced neutrophil mNEP compared to controls (p < 0.01). NEP activity on peripheral blood cells was almost 4-fold higher compared to plasma NEP activity (p = 0.031) and correlated with neutrophil mNEP (p = 0.006). Lower neutrophil mNEP was associated with increasing disease severity and markers of adverse remodeling. Higher neutrophil mNEP was associated with reduced risk for mortality, total cardiovascular hospitalizations, and the composite endpoint of both (p < 0.01 for all). This is the first report describing a significant role of neutrophil mNEP in HFrEF. The biological relevance of neutrophil mNEP and exact effects of angiotensin-converting-enzyme inhibitors (ARNi) at the neutrophil site have to be determined. However, the results may suggest early initiation of ARNi already in less severe HF disease, where effects of NEP inhibition may be more pronounced.

Principal Morphomic and Functional Components of Secondary Mitral Regurgitation.

OBJECTIVES: The aim of this work was to identify the key morphological and functional features in secondary mitral regurgitation (sMR) and their prognostic impact on outcome. BACKGROUND: Secondary sMR in patients with heart failure and reduced ejection fraction typically results from distortion of the underlying cardiac architecture. The morphological components which may account for the clinical impact of sMR have not been systematically assessed or correlated with clinical outcomes. METHODS: Morphomic and functional network profiling were performed on a cohort of patients with stable heart failure optimized on guideline-based medical therapy. Principal component (PC) analysis and subsequent cluster analysis were used to condense the morphomic and functional data first into PCs with varimax rotation (PCVmax) and second into homogeneous clusters. Clusters and PCs were tested for their correlations with clinical outcomes. RESULTS: Morphomic and functional data from 383 patients were profiled and subsequently condensed into PCs. PCVmax 1 describes high loadings of left atrial morphological information, and PCVmax 2 describes high loadings of left ventricular (LV) topology. Based on these components, 4 homogeneous clusters were derived. sMR was most prominent in clusters 3 and 4, with the morphological difference being left ventricular size (median end-diastolic volume 188 mL [interquartile range: 160 mL-224 mL] vs 315 mL [264 mL-408 mL]; P < 0.001). Clusters were associated with mortality (P < 0.001), but sMR remained independently associated with mortality after adjusting for the clusters (adjusted HR: 1.42; 95% CI: 1.14-1.77; P < 0.01). The detrimental association of sMR with mortality was mainly driven by cluster 3 (HR: 2.18; 95% CI: 1.32-3.60; P = 0.002), the "small LV cavity" phenotype. CONCLUSIONS: These results challenge the current perceptions that sMR in heart failure with reduced ejection fraction results exclusively from global or local LV remodeling and are suggestive of a potential role of the left atrial component. The association of sMR with mortality cannot be purely attributed to cardiac morphology alone, supporting other complementary key aspects of mitral valve closure consistent with the force balance theory. Unsupervised clustering supports the association of sMR with mortality predominantly driven by the small LV cavity phenotype, as previously suggested by a conceptional framework and termed disproportionate sMR.

Neprilysin inhibition does not alter dynamic of proenkephalin-A 119-159 and pro-substance P in heart failure.

AIMS: As NEP degrades many substrates, the specific therapeutic mechanism of NEP inhibition with angiotensin receptor neprilysin inhibitor (ARNi) in heart failure with reduced ejection fraction (HFrEF) is not entirely evident. The aim of this study was to investigate the response of two substrates of NEP-the tachykinin and enkephalin systems-to the initiation of ARNi therapy in HFrEF. METHODS AND RESULTS: Between 2016 and 2018, 141 consecutive patients with stable HFrEF [74 with initiation of ARNi and 67 controls on continuous angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy] were prospectively enrolled. Plasma proenkephalin-A 119-159 (PENK) and pro-substance P (pro-SP) were serially determined. Proenkephalin-A 119-159 and pro-SP correlated strongly with each other (rs  = 0.67, P < 0.001) and kidney function (rs  = -0.66, P < 0.001 and rs  = -0.54, P < 0.001) and modestly with NT-proBNP (rs  = 0.32, P < 0.001 and rs  = 0.24, P = 0.006, respectively). Concentrations of circulating PENK were slightly elevated after 1 and 2 year follow-up compared with baseline (BL) [BL median: 67.4 pmol/L (IQR: 57.3-89.8), 1 year: 83.5 pmol/L (IQR: 62.4-111.6), 2 years: 92.3 pmol/L (IQR: 63.1-101.9); BL vs. 1 year: P = 0.017 and BL vs. 2 years: P = 0.019] in the overall analysis, but lost significance at 2 year follow-up when assessed in paired subanalysis (P = 0.116). Plasma pro-SP levels remained comparable during the entire follow-up [BL median: 78.3 pmol/L (IQR: 67.9-90.6), 1 year: 75.9 pmol/L (IQR: 58.6-96.3), 2 years: 79.7 pmol/L (IQR: 59.9-105.3); P = ns for both timepoints]. Biomarker patterns of ARNi patients were independent from baseline therapy, that is, ACEi or ARB (P > 0.05 between groups). CONCLUSIONS: Although enkephalins and SP are known substrates of NEP, NEP inhibition by ARNi does not clearly affect the circulating precursors PENK and pro-SP in HFrEF.

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin-receptor/neprilysin-inhibitor treatment in chronic systolic heart failure.

AIMS: The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi. METHODS: Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up. RESULTS: Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7-37.5] vs. 50.8 [IQR: 36.5-78.1] vs. 54.6 [IQR: 42.0-97.1] vs. 57.4 [IQR: 48.5-161.6]; MR-proADM [nmol/L]: 0.87 [IQR: 0.64-1.12] vs. 1.25 [IQR: 0.93-1.79] vs. 1.42 [IQR: 0.95-1.90] vs. 1.60 [IQR: 1.12-2.46], P < .0001 for all). The ratios bio-ADM/MR-proADM and BNP/NT-proBNP increased during ARNi-therapy proving improved availability of bioactive peptides. The proportional increase of bio-ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin-angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM-axis arises particularly from NEPinhibition. CONCLUSION: The significant increase of MR-proADM and bio-ADM together with an elevated bioADM/MR-proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM-axis represents a so far unrecognized effect of ARNi.

Plasma Neprilysin Displays No Relevant Association With Neurohumoral Activation in Chronic HFrEF.

Background Neprilysin is a transmembrane endopeptidase involved in the breakdown of a variety of vasoactive peptides and serves as a therapeutic target in heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate the relationship of circulating neprilysin with neurohumoral activation and the impact of plasma neprilysin activity on prognosis in HFrEF. Methods and Results A total of 369 chronic HFrEF patients were enrolled prospectively. Plasma neprilysin concentration and activity were determined by a specific ELISA and a fluorometric method. The association between plasma neprilysin and heart failure (HF) severity, neurohumoral activation, ie norepinephrine and absolute renin concentration, as well as all-cause mortality was assessed. Median plasma neprilysin concentrations and activity levels were 413 pg/mL (interquartile range 0-4111) and 2.36 nmol/mL per minute (interquartile range 1.16-4.59). No correlation could be shown between plasma neprilysin concentrations and activity (rs=0.09, P=0.088). Plasma neprilysin activity correlated with HF severity reflected by New York Heart Association stage (P=0.003) and tertiles of N-terminal pro-B-type natriuretic peptide (P<0.001), whereas neprilysin concentrations did not (P=0.220; P=0.849). There was no relevant relationship between plasma neprilysin concentrations and activity, with neurohumoral activation reflected by absolute renin concentration (rs=-0.02, P=0.648; rs=0.03, P=0.574) or norepinephrine levels (rs=-0.06, P=0.248; rs=0.20, P<0.001). Neither circulating neprilysin concentrations nor activity were associated with outcome. Conclusions Plasma neprilysin concentrations and activity are not directly related to neurohumoral activation, indicating that neprilysin regulation is either more complex or not correctly mirrored by circulating neprilysin as a biomarker. Circulating neprilysin concentrations and activity were not associated with overall survival, implicating limited prognostic value of plasma neprilysin measurements in HFrEF patients.

Increased resting heart rate and prognosis in treatment-naïve unselected cancer patients: results from a prospective observational study.

AIMS: Cancer patients suffer from impaired cardiovascular function. Elevated resting heart rate (RHR) has been identified as a marker for increased long-term mortality in cancer patients prior to the receipt of anticancer treatment. We aimed to establish whether RHR is associated with survival in treatment-naïve cancer patients. METHODS AND RESULTS: This prospective study enrolled 548 unselected treatment-naïve cancer patients between 2011 and 2013. The median age of the cohort was 62 years; 40.9% were male and 32.7% had metastatic disease. Median RHR was 72 b.p.m. Most patients were in sinus rhythm (n = 507, 92.5%). Clinical heart failure was noted in 37 (6.8%) patients. RHR was not related to cancer stage (P = 0.504). Patients in the highest RHR tertile had higher levels of high-sensitivity troponin (P = 0.003) and N-terminal pro-B-type natriuretic peptide (P = 0.039). During a median follow-up of 25 months (interquartile range: 16-32 months; range: 0-40 months), 185 (33.8%) patients died from any cause [1-year-mortality: 17%, 95% confidence interval (CI) 13-20%]. In univariate survival analysis, RHR predicted all-cause mortality [crude hazard ratio (HR) for a 5 b.p.m. increase in RHR: 1.09, 95% CI 1.04-1.15; P < 0.001], and remained significantly associated with outcome after adjustment for age, gender, tumour entity, tumour stage, cardiac status and haemoglobin (adjusted HR for a 5 b.p.m. increase in RHR: 1.10, 95% CI 1.04-1.16; P < 0.001). There was no significant impact of metastatic/non-metastatic disease state on the predictive value of RHR (P = 0.433 for interaction). In subgroup analyses, the strongest associations for RHR with mortality were observed in lung (crude HR 1.14; P = 0.007) and gastrointestinal (crude HR 1.31; P < 0.001) cancer. CONCLUSIONS: Treatment-naïve cancer patients with higher RHRs display higher levels of cardiovascular biomarkers. RHR was independently associated with all-cause mortality, especially in lung and gastrointestinal cancers. Elevated RHR and cardiovascular biomarkers may represent early signs of incipient cardiac dysfunction.

The inflammation-based modified Glasgow prognostic score is associated with survival in stable heart failure patients.

AIMS: The progression of heart failure is presumably dependent on the individual inflammatory host response. The combination of the inflammatory markers, albumin, and C-reactive protein, termed modified Glasgow prognostic score (mGPS), has been derived from cancer patients and validated in multiple cohorts. This study aimed to investigate the impact of the easily available mGPS on survival of stable patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Patients with stable HFrEF undergoing routine ambulatory care between January 2011 and November 2017 have been identified from a prospective registry at the Medical University of Vienna. Comorbidities, laboratory data as well as the nutritional risk index at baseline were assessed. All-cause mortality was defined as the primary study end point. The mGPS was calculated, and its association with heart failure severity and impact on overall survival were determined. Data were analysed for a total of 443 patients. The mGPS was 0 for 352 (80%), 1 for 76 (17%), and 2 for 14 (3%) patients, respectively. Elevation of mGPS was associated with worsening of routine laboratory parameters linked to prognosis, especially NT-proBNP [median 1830 pg/mL (IQR 764-3455) vs. 4484 pg/mL (IQR 1565-8003) vs. 6343 pg/mL (IQR 3750-15401) for mGPS 0, 1, and 2, respectively; P < 0.001] and nutritional risk index. In the Cox regression analysis, the increase of mGPS was associated with adverse outcome in the univariate analysis [crude hazard ratio 3.00 (95% CI 2.14-4.21), P < 0.001] and after adjustment for multiple covariates as age, gender, body mass index, and glomerular filtration rate as well as heart failure severity reflected by NT-proBNP and New York Heart Association class [adj. hazard ratio 1.87 (95% CI 1.19-2.93), P = 0.006]. CONCLUSIONS: Enhanced inflammation and nutritional depletion are more common in advanced heart failure. The inflammation-based score mGPS predicts survival in HFrEF patients independently of NT-proBNP emphasizing the significance of the individual pro-inflammatory response on prognosis.

GDF-15 in solid vs non-solid treatment-naïve malignancies.

AIM: GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients. METHODS: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint. RESULTS: GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease. CONCLUSIONS: Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.

A Unifying Concept for the Quantitative Assessment of Secondary Mitral Regurgitation.

BACKGROUND: Diverging guideline definitions for the quantitative assessment of severe secondary mitral regurgitation (sMR) reflect the lacking link of the sMR spectrum to mortality and has introduced a source of uncertainty and continuing debate. OBJECTIVES: The current study aimed to define improved risk-thresholds specifically tailored to the complex nature of sMR that provide a unifying solution to the ongoing guideline-controversy. METHODS: This study enrolled 423 heart failure patients under guideline-directed medical therapy and assessed sMR by effective regurgitant orifice area (EROA), regurgitant volume (RegVol), and regurgitant fraction (RegFrac). RESULTS: Measures of sMR severity were consistently associated with 5-year mortality with a hazard ratio of 1.42 for a 1-SD increase (95% confidence interval [CI]: 1.25 to 1.63; p < 0.001) for EROA, 1.37 (95% CI: 1.20 to 1.56; p < 0.001) for RegVol, and 1.50 (95% CI: 1.30 to 1.73; p < 0.001) for RegFrac. Results remained statistically significant after bootstrap- or clinical confounder-based adjustment. Spline-curve analyses showed a linearly increasing risk enabling the ability to stratify into low-risk (EROA <20 mm2 and RegVol <30 ml), intermediate-risk (EROA 20 to 29 mm2 and RegVol 30 to 44 ml), and high-risk (EROA ≥30 mm2 and RegVol ≥45 ml) groups. In the intermediate-risk group, a RegFrac ≥50% as indicator for hemodynamic severe sMR was associated with poor outcome (p = 0.017). A unifying concept based on combined assessment of the EROA, the RegVol, and the RegFrac showed a significantly better discrimination compared with the currently established algorithms. CONCLUSIONS: Risk-based thresholds tailored to the pathophysiological concept of sMR provide a unifying solution to the ongoing guideline controversy. An algorithm based on the combined assessment of the unifying cutoffs for EROA, RegVol, and RegFrac improves risk prediction compared with currently established grading.

The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naïve cancer patients.

The transmembrane zink-metalloendopeptidase neprilysin (NEP) is implicated in cardiovascular disease but also tumor biology. The aim of the study was to investigate the relationship of circulating NEP (cNEP) levels with established cardiovascular biomarkers and its effect on overall survival in an unselected cohort of treatment-naïve cancer patients. 555 consecutive cancer patients prior anticancer therapy were enrolled prospectively. NEP levels were determined alongside routine laboratory parameters, established cardiac biomarkers, i.e. NT-proBNP, hsTnT, MR-proANP, MR-proADM, CT-proET-1 and Copeptin, and inflammatory parameters, i.e. CRP, IL-6 and SAA, in venous plasma samples. All-cause mortality was the primary endpoint. cNEP levels of 276 pg/ml (IQR: 0-5981) displayed a weak inverse correlation with age [r = -0.12, p = 0.023] and inflammatory status [r = -0.14, p = 0.007 CRP; r = -0.20, p < 0.001 IL-6 and r = -0.18, p < 0.001 SAA]. cNEP was comparable between different tumor entities and stages and not related to functional parameters of other organ systems as kidney, liver or especially the heart. Moreover, cNEP was not associated with overall survival in the total cohort [adj.HR for ln (cNEP) 1.00, 95% CI: 0.94-1.06, p = 0.887] but in myelodysplatic malignancies [adj.HR for ln (cNEP) 1.27, 95% CI: 1.01-1.61, p = 0.044]. In conclusion, cNEP lacks association with outcome but for myelodysplastic disease. cNEP shows no correlation with established cardiovascular biomarkers related to prognosis, thereby holding a limited potential as a biomarker in cardio-oncology.

N-terminal B-type natriuretic peptide (NT-proBNP) is associated with disease severity in multiple myeloma.

BACKGROUND: Elevated levels of cardiovascular markers including N-terminal B-type natriuretic peptide (NT-proBNP) have been shown to be associated with disease severity and mortality in an unselected population of cancer patients without cardiac disease. The aim of this study was to investigate whether NT-proBNP levels are related to disease severity in multiple myeloma (MM) and to assess the natural course of NT-proBNP levels throughout disease progression. MATERIALS AND METHODS: We retrospectively analysed a total of 118 patients with MM, who were followed up routinely. NT-proBNP, beta-2-microglobulin (B2M) and levels of plasma cell-derived light chains were measured at baseline and follow-up (FUP) visits. All-cause mortality was defined as primary study endpoint, and the correlation between NT-proBNP and disease severity reflected by B2M and the International Staging System (ISS) was assessed. RESULTS: During a median FUP of 845 (IQR:683-978) days, 31 patients (26%) died. NT-proBNP showed a highly significant positive correlation with B2M at first presentation [r = .65, P < .001] and increased significantly with progressing MM disease stage [133.3 pg/mL (IQR:51.5-282.0) for ISS stage 1, 487.4 pg/mL (IQR:123.8-738.3) for ISS stage 2 and 969.1 pg/mL (IQR:472.8-3748.0) for ISS stage 3, P < .001 between all groups]. During FUP, NT-proBNP levels rose significantly alongside other MM disease severity markers for patients experiencing the primary outcome [356.6 pg/mL (IQR:142.9-782.3) vs 862.9 pg/mL (IQR:338.8-4215.0), P < .001], whereas no significant changes in laboratory parameters could be detected for survivors. CONCLUSIONS: Elevated levels of the cardiovascular marker NT-proBNP are associated with disease severity in patients with MM.

Subclinical involvement of the liver is associated with prognosis in treatment naïve cancer patients.

BACKGROUND: Routinely tested liver biomarkers as alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), butyryl-cholinesterase (BChE), albumin and bilirubin are altered in distinct malignancies and hepatic metastases. This study aimed to investigate whether all liver parameters have the ability to predict long-term mortality in treatment naïve cancer patients but without a malignant hepatic involvement. METHODS: We prospectively enrolled 555 consecutive patients with primary diagnosis of cancer without prior anticancer therapy. BChE, albumin, AST, ALT, GGT and bilirubin as well as the inflammatory makers C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) were determined. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR16-31) months 186 (34%) patients died. All liver parameters were significantly associated with all-cause mortality (p < 0.001 for all). However, for patients without a malignant primary or secondary hepatic involvement (82%) only the functional parameters BChE and albumin remained significantly associated with the primary endpoint (crude HR per 1-IQR increase 0.61, 95%CI:0.49-0.77; p < 0.001 for BChE and 0.58, 95%CI:0.47-0.70; p < 0.001 for albumin). This e ect was persistent after multivariate adjustment (adj.HR per 1-IQR increase 0.65, 95%CI:0.50-0.86; p = 0.002 for BChE and 0.63, 95%CI:0.50-0.79; p < 0.001 for albumin). BChE and albumin correlated inversely with CRP (r = -0.21, p < 0.001 and r = -0.36, p < 0.001), SAA (r = -0.19, p < 0.001 and r = -0.33, p < 0.001) and IL-6 (r = -0.13, p = 0.009 and r = -0.17, p = 0.001). CONCLUSIONS: Decreased serum BChE and albumin levels are associated with increased all-cause mortality in treatment-naïve cancer patients without a manifest malignant hepatic involvement irrespective of tumor entity or stage. This association may reflect progressing systemic inflammation and metabolic derangement with subclinical involvement of the liver.

GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer-free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes.

Cardiovascular safety of metformin and sulfonylureas in patients with different cardiac risk profiles.

OBJECTIVES/BACKGROUND: Based on previous experiences, the Food and Drug Administration and the European Medicines Agency recommend that clinical trials for novel antidiabetic drugs are powered to detect increased cardiovascular risk. In this context, data concerning licensed drugs such as metformin and sulfonylureas are conflicting. The influence of baseline cardiovascular risk on any treatment effect appears obvious but has not been formally proven. We therefore evaluated association of metformin and sulfonylureas with cardiovascular events in patients with different cardiovascular risk profiles indicated by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels. METHODS: 2024 patients with diabetes mellitus were included in this observational study. The primary endpoint was defined as a combination of cardiovascular events and death. Association of metformin and sulfonylureas was assessed using Cox regression models. Possible differences of these associations in patients with different NT-proBNP levels were studied by stratifying and through interaction analysis. RESULTS: During a median follow-up of 60 months, the primary endpoint occurred in 522 (26%) of patients. The median age was 63 years. A Cox regression analysis was adjusted for site of treatment, concomitant medication, age, gender, body mass index, glycated haemoglobin, duration of diabetes, glomerular filtration rate, cholesterol, and history of smoking and cardiac disease. Metformin was associated with a decreased risk in the cohort with elevated NT-proBNP ≥300 pg/mL (HR 0.70, p=0.014) and a similar association was found for the interaction between metformin and NT-proBNP (p=0.001). There was neither an association for sulfonylureas nor a significant interaction between sulfonylureas and NT-proBNP. CONCLUSIONS: Metformin is associated with beneficial cardiovascular outcomes in patients with diabetes only when (sub)clinical cardiovascular risk defined by NT-proBNP levels is present.

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

OBJECTIVE: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. METHODS: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. CONCLUSIONS: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Attitude is everything? The impact of workload, safety climate, and safety tools on medical errors: a study of intensive care units.

BACKGROUND: Hospitals face an increasing pressure toward efficiency and cost reduction while ensuring patient safety. This warrants a closer examination of the trade-off between production and protection posited in the literature for a high-risk hospital setting (intensive care). PURPOSES: On the basis of extant literature and concepts on both safety management and organizational/safety culture, this study investigates to which extent production pressure (i.e., increased staff workload and capacity utilization) and safety culture (consisting of safety climate among staff and safety tools implemented by management) influence the occurrence of medical errors and if/how safety climate and safety tools interact. METHODOLOGY/APPROACH: A prospective, observational, 48-hour cross-sectional study was conducted in 57 intensive care units. The dependent variable is the incidence of errors affecting those 378 patients treated throughout the entire observation period. Capacity utilization and workload were measured by indicators such as unit occupancy, nurse-to-patient/physician-to-patient ratios, levels of care, or NEMS scores. The safety tools considered include Critical Incidence Reporting Systems, audits, training, mission statements, SOPs/checklists, and the use of barcodes. Safety climate was assessed using a psychometrically validated four-dimensional questionnaire.Linear regression was employed to identify the effects of the predictor variables on error rate as well as interaction effects between safety tools and safety climate. FINDINGS: Higher workload has a detrimental effect on safety, whereas safety climate-unlike the examined safety tools-has a virtually equal opposite effect. Correlations between safety tools and safety climate as well as their interaction effects on error rate are mostly nonsignificant. PRACTICE IMPLICATIONS: Increased workload and capacity utilization increase the occurrence of medical error, an effect that can be offset by a positive safety climate but not by formally implemented safety procedures and policies.