A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia.

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

Ropeginterferon phase 2 randomized study in low-risk polycythemia vera: 5-year drug survival and efficacy outcomes.

In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 µg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis.

Total NT-proBNP, a novel biomarker related to recurrent atrial fibrillation.

BACKGROUND: Novel circulating biomarkers may help in understanding the underlying mechanisms of atrial fibrillation (AF), a challenge for AF management and prevention of cardiovascular (CV) events. Whether glycosylation affects the prognostic value of N-terminal pro-B type natriuretic peptide (NT-proBNP) in AF is still unknown. OBJECTIVES: To test how deglycosylated total NT-proBNP, NT-proBNP and a panel of biomarkers are associated with: (1) recurrent AF, (2) first hospitalization for CV reasons. METHODS: A total of 382 patients of the GISSI-AF trial in sinus rhythm with a history of AF, echocardiographic variables, total NT-proBNP, NT-proBNP and nine additional biomarkers [Total N-terminal pro-B type natriuretic peptide (Total NT proBNP), N-terminal pro-B type natriuretic peptide (NTproBNP), Angiopoietin 2 (Ang2), Bone morphogenic protein-10 (BMP10), Dickkopf-related protein-3 (DKK3), Endothelial cell specific molecule-1 (ESM1), Fatty acid-binding protein 3 (FABP3), Fibroblast growth factor 23 (FGF23), Growth differentiation factor-15 (GDF15), Insulin-like growth factor-binding protein-7 (IGFBP7) and Myosin binding protein C3 (MYPBC3)]. were assayed at baseline, 6 and 12 months under blind conditions in a laboratory at Roche Diagnostics, Penzberg, Germany. The associations between circulating biomarkers and AF at the 6- and 12-month visits, and their predictive value, were assessed in multivariable models with logistic regression analysis and Cox proportional hazards regression analysis. Biomarkers associations were modelled for 1SD increase in their level. RESULTS: Over a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for CV reasons. Total NT-proBNP, NT-proBNP, Ang2 and BMP10 showed the strongest associations with ongoing AF. Natriuretic peptides also predicted recurrent AF (total NT-proBNP: HR:1.19[1.04-1.36], p = 0.026; NT-proBNP: HR:1.19[1.06-1.35], p = 0.016; Ang2: HR:1.07[0.95-1.20], p = 0.283; BMP10: HR:1.09[0.96-1.25], p = 0.249) and CV hospitalization (total NT-proBNP: HR:1.57[1.29-1.90], p < 0.001 1.63], p = 0.097). CONCLUSIONS: The association of total NT-proBNP with the risk of AF first recurrence was similar to that of NT-proBNP, suggesting no influence of glycosylation. Analogous results were obtained for the risk of first hospitalization for CV reasons. Natriuretic peptides, Ang2 and BMP10 were associated with ongoing AF. Findings from the last two biomarkers point to a pathogenic role of cardiac extracellular matrix and cardiomyocyte growth in the myocardium of the right atrium and ventricle.

Paediatric emergencies and related mortality in Nicaragua: results from a multi-site paediatric emergency registry.

BACKGROUND: We aim to describe the characteristics and outcomes of the severe spectrum of paediatric emergency visits using a multi-site registry developed as part of an international cooperation project. METHODS: This observational registry-based study presented descriptive statistics of clinical and outcome data on urgent-emergency paediatric visits from 7 Nicaraguan hospitals, including the national referral paediatric hospital, between January and December 2017. Extensive piloting to ensure data collection feasibility, sustainability and accuracy was carried out in 2016 with substantial input and feedback from local stakeholders. RESULTS: Overall, 3521 visits of patients <15 years of age, of whom two-thirds <5 years, met predefined inclusion criteria of urgent-emergency visits. Respiratory (1619/3498; 46%), gastrointestinal (407/3498; 12%) and neurological (368/3498; 11%) complaints were the most common symptoms. Malnutrition was reported in 18% (610/3448) of presentations. Mortality was 7% (233/3521); 52% (120/233) of deaths occurred in the <1-year subgroup; 32% (71/3521) of deaths occurred within the first 24 hours of presentation. The most common immediate causes of death were septic shock (99/233; 43%), respiratory failure (58/233; 25%) and raised intracranial pressure (24/233; 10%). CONCLUSIONS: The mortality rate of urgent-emergency paediatric visits in Nicaragua is high, with younger children being most at risk and the majority of deaths being eventually caused by septic shock or respiratory failure. Our data provide useful information for the development of a Paediatric Emergency Care network to help direct training efforts, resources and logistic/organisational interventions to improve children's health in an emergency setting in Nicaragua.

Cardiovascular mortality and morbidity burden in successive and age pre-stratified case-control cohorts of breast cancer women. A population-based study.

AIMS: To assess the existence, components and clinical relevance of cardiac causes of death and cardiovascular (CV) hospitalizations in a population-wide database of patients with breast cancer (BC). METHODS AND RESULTS: A population-wide database of the Puglia Region, Italy was analyzed, with a prospective comparative design. Three successive closely matched case/control cohorts representing current care in the period 2007-2014 were also stratified according to age to focus specifically on the potential interaction of treatment-related cardiac toxicity and the expected different baseline CV risk profiles. RESULTS: At 3-year follow-up, in the successive cohorts the incidence of BC-related (7.7, 7.0, 6.5%) and cardiac causes of death, specifically attributed to heart failure (HF, 1.3, 0.5, 0.5%), decreased. Significant mortality hazard ratio (HR) for HF was found in the total population (1.47, 95% CI 1.14-1.90), in particular in the 2007-2009 cohort (1.71, 95% CI 1.19-2.46) and in the 50-69 age group (7.96, 95% CI 2.81-22.55). Results at 5 years confirm the mortality findings, and a significant HR for hospitalizations for HF, non-atrial arrhythmias and ischemic heart disease in the younger than 50 subpopulation pointed to a late expression of toxicity in the youngest BC population. CONCLUSIONS: The incidence of CV causes of death 3 and 5 years after BC diagnosis was very low, even if an excess in risk of death for HF as compared with the control cohort was observed. While younger patients seems to tolerate BC and BC therapy better in the short term, HF mortality and morbidity resulted significantly increased at 5-year follow-up. As the risk for hospitalization for CV reasons increased at 5-year follow-up in particular in women aged less than 50 years, CV monitoring in this subgroup of patients seems mandatory.

Health as a Human Right: A Fake News in a Post-human World?

Based on a synthetic overview that embraces the evolution of the 'health' concept, and its related institutions, from the role of health as the main indicator of fundamental human rights-as envisaged in the Universal Declaration of Human Rights-to its qualification as the systems of disease control dependent on criteria of economic sustainability, the paper focuses on the implications and the impact of such evolution in two model scenarios which are centred on the COVID-19 pandemia. The article analyses COVID-19 both in the characteristics of its global dynamics and in its concrete management, as performed in a model medium income country, Argentina. In a world which has progressively assigned market values and goods an absolute strategic and political priority over the health needs and the rights to health of individual and peoples, the recognition of health as human right is confined to aspirational recommendations and rather hollowed out declarations of good will.

Prognostic Value of High-Sensitivity Troponin T in Chronic Heart Failure: An Individual Patient Data Meta-Analysis.

BACKGROUND: Most patients with chronic heart failure have detectable troponin concentrations when evaluated by high-sensitivity assays. The prognostic relevance of this finding has not been clearly established so far. We aimed to assess high-sensitivity troponin assay for risk stratification in chronic heart failure through a meta-analysis approach. METHODS: Medline, EMBASE, Cochrane Library, and Scopus were searched in April 2017 by 2 independent authors. The terms were "troponin" AND "heart failure" OR "cardiac failure" OR "cardiac dysfunction" OR "cardiac insufficiency" OR "left ventricular dysfunction." Inclusion criteria were English language, clinical stability, use of a high-sensitivity troponin assay, follow-up studies, and availability of individual patient data after request to authors. Data retrieved from articles and provided by authors were used in agreement with the PRISMA statement. The end points were all-cause death, cardiovascular death, and hospitalization for cardiovascular cause. RESULTS: Ten studies were included, reporting data on 11 cohorts and 9289 patients (age 66±12 years, 77% men, 60% ischemic heart failure, 85% with left ventricular ejection fraction <40%). High-sensitivity troponin T data were available for all patients, whereas only 209 patients also had high-sensitivity troponin I assayed. When added to a prognostic model including established risk markers (sex, age, ischemic versus nonischemic etiology, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal fraction of pro-B-type natriuretic peptide), high-sensitivity troponin T remained independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.41-1.55), cardiovascular mortality (hazard ratio, 1.40; 95% confidence interval, 1.33-1.48), and cardiovascular hospitalization (hazard ratio, 1.42; 95% confidence interval, 1.36-1.49), over a median 2.4-year follow-up (all P<0.001). High-sensitivity troponin T significantly improved risk prediction when added to a prognostic model including the variables above. It also displayed an independent prognostic value for all outcomes in almost all population subgroups. The area under the curve-derived 18 ng/L cutoff yielded independent prognostic value for the 3 end points in both men and women, patients with either ischemic or nonischemic etiology, and across categories of renal dysfunction. CONCLUSIONS: In chronic heart failure, high-sensitivity troponin T is a strong and independent predictor of all-cause and cardiovascular mortality, and of hospitalization for cardiovascular causes, as well. This biomarker then represents an additional tool for prognostic stratification.

Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The use of aspirin in the primary prevention of cardiovascular events remains controversial. We aimed to assess the efficacy and safety of aspirin versus placebo in patients with a moderate estimated risk of a first cardiovascular event. METHODS: ARRIVE is a randomised, double-blind, placebo-controlled, multicentre study done in seven countries. Eligible patients were aged 55 years (men) or 60 years (women) and older and had an average cardiovascular risk, deemed to be moderate on the basis of the number of specific risk factors. We excluded patients at high risk of gastrointestinal bleeding or other bleeding, or diabetes. Patients were randomly assigned (1:1) with a computer-generated randomisation code to receive enteric-coated aspirin tablets (100 mg) or placebo tablets, once daily. Patients, investigators, and others involved in treatment or data analysis were masked to treatment allocation. The primary efficacy endpoint was a composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischaemic attack. Safety endpoints were haemorrhagic events and incidence of other adverse events, and were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00501059. FINDINGS: Between July 5, 2007, and Nov 15, 2016, 12 546 patients were enrolled and randomly assigned to receive aspirin (n=6270) or placebo (n=6276) at 501 study sites. Median follow-up was 60 months. In the intention-to-treat analysis, the primary endpoint occurred in 269 (4·29%) patients in the aspirin group versus 281 (4·48%) patients in the placebo group (hazard ratio [HR] 0·96; 95% CI 0·81-1·13; p=0·6038). Gastrointestinal bleeding events (mostly mild) occurred in 61 (0·97%) patients in the aspirin group versus 29 (0·46%) in the placebo group (HR 2·11; 95% CI 1·36-3·28; p=0·0007). The overall incidence rate of serious adverse events was similar in both treatment groups (n=1266 [20·19%] in the aspirin group vs n=1311 [20·89%] in the placebo group. The overall incidence of adverse events was similar in both treatment groups (n=5142 [82·01%] vs n=5129 [81·72%] in the placebo group). The overall incidence of treatment-related adverse events was low (n=1050 [16·75%] vs n=850 [13·54%] in the placebo group; p<0·0001). There were 321 documented deaths in the intention-to-treat population (n=160 [2·55%] vs n=161 [2·57%] of 6276 patients in the placebo group). INTERPRETATION: The event rate was much lower than expected, which is probably reflective of contemporary risk management strategies, making the study more representative of a low-risk population. The role of aspirin in primary prevention among patients at moderate risk could therefore not be addressed. Nonetheless, the findings with respect to aspirin's effects are consistent with those observed in the previously published low-risk primary prevention studies. FUNDING: Bayer.

Modes of death and prognostic outliers in chronic heart failure.

BACKGROUND: The impact of incident sudden cardiac death (SCD) on the predictive accuracy of prognostic risk scores for patients with chronic heart failure (HF) has rarely been examined. We assessed the relationship between estimated probability of death and modes of death in this population, as well as the predictors of death and survival in prognostic outliers. METHODS AND RESULTS: The MAGGIC 3-year probability of death was estimated in 6,859 participants of the GISSI-HF trial (mean age 67±11 years, 78% men, 91% with ejection fraction <40%, mean follow-up 3.5±1.3 years, observed mortality 28.4%). The incidence of SCD progressively decreased with increased probability of death, and occurred in 52.5% of patients estimated at low-risk (N = 61 with probability <14%) vs. in 23.5% of the high-risk ones (N = 375 with probability >56%, P < .0001). On the contrary, death from worsening HF was significantly more frequent in the latter group (19.7% vs. 46.1%, P < .0001). The overall predictive accuracy of the MAGGIC model improved after excluding deaths from SCD (AUC from 0.731 to 0.760, P = .0034). Among patients estimated at low-risk (N = 61 dead, 743 alive), independent predictors of death were older age, longer history of HF, higher serum uric acid and chronic obstructive pulmonary disease. The only predictor of survival in patients estimated at high-risk (N = 210 alive, 375 dead) was higher systolic blood pressure. CONCLUSIONS: The MAGGIC risk score demonstrated its scarce ability to capture SCD, particularly in chronic HF patients estimated at low risk of death. Newer and better prognostic tools in the evolving horizon of HF are needed.

The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial.

BACKGROUND: The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. METHODS: In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP<130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. RESULTS: Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). CONCLUSIONS: Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.

Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis.

OBJECTIVE: Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis. DESIGN: Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). SETTING: Forty ICUs in Italy. PATIENTS: Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 × 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 10/L who developed thrombocytopenia (≤ 50 × 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 10/L (n = 95). INTERVENTIONS: Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1. MEASUREMENTS AND MAIN RESULTS: Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality. CONCLUSIONS: Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.

Circulating Proenkephalin, Acute Kidney Injury, and Its Improvement in Patients with Severe Sepsis or Shock.

BACKGROUND: Acute kidney injury (AKI) occurs in many critically ill patients and is associated with high mortality. We examined whether proenkephalin could predict incident AKI and its improvement in septic patients. METHODS: Plasma proenkephalin A 119-159 (penKid) was assayed in 956 patients with sepsis or septic shock enrolled in the multicenter Albumin Italian Outcome Sepsis (ALBIOS) trial to test its association with incident AKI, improvement of renal function, need for renal replacement therapy (RRT), and mortality. RESULTS: Median [Q1-Q3] plasma penKid concentration on day 1 [84 (20-159) pmol/L[ was correlated with serum creatinine concentration (r = 0.74); it was higher in patients with chronic renal failure and rose progressively with the renal Sequential Organ Failure Assessment subscore. It predicted incident AKI within 48 h (adjusted odds ratio, 3.3; 95% CI, 2.1-5.1; P < 0.0001) or 1 week [adjusted hazard ratio, 2.1 (1.7-2.8); P < 0.0001] and future RRT during the intensive care unit stay [odds ratio, 4.0 (3.0-5.4)]. PenKid was also associated with improvements in renal function in patients with baseline serum creatinine >2 mg/dL, both within the next 48 h [adjusted odds ratio, 0.31 (0.18-0.54), P < 0.0001] and 1 week [0.23 (0.12-0.45)]. The time course of penKid concentrations predicted AKI and 90-day mortality. CONCLUSIONS: Early measurement and the trajectory of penKid predict incident AKI, improvement of renal function, and the need for RRT in the acute phase after intensive care unit admission during sepsis or septic shock. PenKid measurement may be a valuable tool to test early therapies aimed at preventing the risk of AKI in sepsis.

Albumin replacement in patients with severe sepsis or septic shock.

BACKGROUND: Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established. METHODS: In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital. RESULTS: During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P=0.03) and lower net fluid balance (P<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (P=0.10). At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (relative risk in the albumin group, 1.00; 95% confidence interval [CI], 0.87 to 1.14; P=0.94). At 90 days, 365 of 888 patients (41.1%) in the albumin group and 389 of 893 (43.6%) in the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85 to 1.05; P=0.29). No significant differences in other secondary outcomes were observed between the two groups. CONCLUSIONS: In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. (Funded by the Italian Medicines Agency; ALBIOS ClinicalTrials.gov number, NCT00707122.).

Clinical and prognostic value of spot urinary creatinine in chronic heart failure-An analysis from GISSI-HF.

OBJECTIVES: This study aimed to identify patient characteristics associated with low urinary creatinine in morning spot urine and investigate its association with clinical outcome. BACKGROUND: Twenty-four-hour creatinine excretion is an established marker of muscle mass in heart failure and other populations. Spot urine creatinine might be an easy obtainable, cheap marker of muscle wasting and prognosis in heart failure (HF) patients. METHODS: Spot urine creatinine concentration was measured in 2130 patients included in the GISSI-HF trial. We evaluated the prognostic value of urinary creatinine and its relation with clinical variables. RESULTS: Median spot urinary creatinine was 0.80 (IQR 0.50-1.10) g/L. Lower spot urinary creatinine was associated with older age, smaller height and weight, higher NYHA class, worse renal function and more frequent spironolactone and diuretic use (all P<.02). During a median follow-up of 2.8 years, 655 patients (31%) experienced the combined endpoint of all-cause mortality or HF hospitalization. Lower urinary creatinine was independently associated with an increased risk of all-cause mortality or HF hospitalization (HR, 1.59 [1.21-2.08] per log decrease, P=.001), and all-cause mortality (HR, 1.75 [1.25-2.45] per log decrease, P=.001). CONCLUSION: Lower urinary creatinine, measured in morning spot urine in patients with chronic HF, is associated with worse renal function, smaller body size, more severe HF and is independently associated with an increased risk of all-cause death and HF hospitalization.

Progression of Renal Impairment and Chronic Kidney Disease in Chronic Heart Failure: An Analysis From GISSI-HF.

BACKGROUND: Data on the natural change in renal function in patients with chronic heart failure (HF) are limited. METHODS AND RESULTS: Estimated glomerular filtration rate (eGFR) was assessed over 36 months in 6934 patients included in the GISSI-HF study. Associations from baseline, changes in renal function, and occurrence of cardiovascular death or HF hospitalization were assessed. Mean age was 67 years, mainly men (78%), and mean eGFR was 68 mL • min-1 • 1.73 m-2. Change in eGFR in the 1st year was -1.5 ± 16 mL • min-1 • 1.73 m-2, and over 36 months it was -3.7 ± 18 mL • min-1 • 1.73 m-2. Over the latter period, only 25% deteriorated ≥1 Kidney Disease Outcomes Quality Initiatives (KDOQI) class of chronic kidney disease (CKD). Fifteen percent of patients had >15 mL • min-1 • 1.73 m-2 decrease in eGFR in the 1st 12 months. Lower eGFR was associated with outcome: hazard ratio (HR) 1.10, 95% confidence interval (CI) 1.08-1.10 (P < .001) per 10 mL • min-1 • 1.73 m-2 decrease, as well as every 10 mL • min-1 • 1.73 m-2 decrease over the 1st year (HR 1.10, 95% CI 1.04-1.17; P < .001). A deterioration in eGFR >15 mL • min-1 • 1.73 m-2 in the 1st year showed the highest risk of events (HR 1.22, 95% CI 1.10-1.36; P < .001). CONCLUSIONS: Mean decrease in renal function over time in patients with chronic HF was modest. Only 25% deteriorated ≥1 KDOQI class of CKD after 3 years. Any decrease in eGFR over time was associated with strongly increased event rates.

Pentraxin 3 in patients with severe sepsis or shock: the ALBIOS trial.

BACKGROUND: The long pentraxin PTX3 is a key component of the humoral arm of innate immunity related to sepsis severity and mortality. We evaluated the clinical and prognostic significance of circulating PTX3 in the largest cohort ever reported of patients with severe sepsis or septic shock. MATERIALS AND METHODS: Plasma PTX3 was measured on days 1, 2 and 7 after randomization of 958 patients to albumin or crystalloids for fluid resuscitation in the multicentre Albumin Italian Outcome Sepsis (ALBIOS) trial. We tested the association of PTX3 and its changes over time with clinical severity, prevalent and incident organ dysfunctions, 90-day mortality and treatment. RESULTS: PTX3 was high at baseline (72 [33-186] ng/mL) and rose with the severity and number of organ dysfunctions (P < 0·001) and the incidence of subsequent new failures. The PTX3 concentration dropped from day 1 to 7, but this decrease was less pronounced in patients with septic shock (P = 0·0004). Higher concentrations of PTX3 on day 1 predicted incident organ dysfunctions. Albumin supplementation was associated with lower levels of PTX3 in patients with septic shock (P = 0·005) but not in those without shock. In a fully adjusted multivariable model, PTX3 on day 7 predicted 90-day mortality. Smaller drops in PTX3 predicted higher 90-day mortality. CONCLUSIONS: In severe sepsis and septic shock, early high PTX3 predict subsequent new organ failures, while a smaller drop in circulating PTX3 over time predicts an increased risk of death. Patients with septic shock show lower levels of PTX3 when assigned to albumin than to crystalloids.

A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: A propensity-matched study.

The use of hydroxyurea (HU) as first line therapy in polycythemia vera (PV) has been criticized because no solid demonstration that this drug prevents thrombosis or prolongs survival has been so far produced. Here we present the outcomes of a large cohort of patients with PV included in the European Collaborative Low-dose Aspirin (ECLAP) study. We selected 1,042 patients who, during the follow-up, had received only phlebotomy (PHL) or HU to maintain the hematocrit level < 45%. To assure comparability, we conducted a propensity score matching analysis. The two groups (PHL n = 342 and HU n = 681) were well balanced for the parameters included in the propensity score (overall balance: χ2 = 2.44, P = 0.964). Over a comparable period of follow-up (PHL = 29.9 vs. HU = 34.7 months), we documented an advantage of HU over PHL consistently significant with respect to the incidence of fatal/non-fatal cardiovascular (CV) events (5.8 vs. 3.0 per 100 person-years in PHL vs. HU group, P = 0.002) and myelofibrosis transformation that was only experienced by patients of PHL group. Evolution to acute leukemia was registered in three patients (two in PHL and one in HU group). The excess of mortality and total CV events in the PHL patients was restricted to the high-risk group, and, compared with HU cases, was significant higher in the PHL patients who failed to reach the hematocrit target < 0.45% (P = 0.000). In conclusion, this analysis provides reliable and qualified estimates of the therapeutic profile of HU and PHL treatments for future experimental studies and for the management of PV in clinical practice.

Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials.

BACKGROUND: Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF). METHODS AND RESULTS: We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by χ(2) value): age (hazard ratio, 1.34; 95% confidence interval, 1.18-1.63 per 10 years), New York Heart Association class (1.60, 1.21-2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22-2.88), body mass index (0.74, 0.60-0.91 per 5 kg/m(2) up to 30), and previous stroke (1.81, 1.19-2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11-1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF. CONCLUSIONS: A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.

n-3 fatty acids in patients with multiple cardiovascular risk factors.

BACKGROUND: Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction. METHODS: In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. RESULTS: Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points. CONCLUSIONS: In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. (Funded by Società Prodotti Antibiotici and others; ClinicalTrials.gov number, NCT00317707.).