Prognostic Value and Relative Cutoffs of Triglycerides Predicting Cardiovascular Outcome in a Large Regional-Based Italian Database.

BACKGROUND: Despite longstanding epidemiologic data on the association between increased serum triglycerides and cardiovascular events, the exact level at which risk begins to rise is unclear. The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension has conceived a protocol aimed at searching for the prognostic cutoff value of triglycerides in predicting cardiovascular events in a large regional-based Italian cohort. METHODS AND RESULTS: Among 14 189 subjects aged 18 to 95 years followed-up for 11.2 (5.3-13.2) years, the prognostic cutoff value of triglycerides, able to discriminate combined cardiovascular events, was identified by means of receiver operating characteristic curve. The conventional (150 mg/dL) and the prognostic cutoff values of triglycerides were used as independent predictors in separate multivariable Cox regression models adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, serum uric acid, arterial hypertension, diabetes, chronic renal disease, smoking habit, and use of antihypertensive and lipid-lowering drugs. During 139 375 person-years of follow-up, 1601 participants experienced cardiovascular events. Receiver operating characteristic curve showed that 89 mg/dL (95% CI, 75.8-103.3, sensitivity 76.6, specificity 34.1, P<0.0001) was the prognostic cutoff value for cardiovascular events. Both cutoff values of triglycerides, the conventional and the newly identified, were accepted as multivariate predictors in separate Cox analyses, the hazard ratios being 1.211 (95% CI, 1.063-1.378, P=0.004) and 1.150 (95% CI, 1.021-1.295, P=0.02), respectively. CONCLUSIONS: Lower (89 mg/dL) than conventional (150 mg/dL) prognostic cutoff value of triglycerides for cardiovascular events does exist and is associated with increased cardiovascular risk in an Italian cohort.

Hypertriglyceridemia is associated with decline of estimated glomerular filtration rate and risk of end-stage kidney disease in a real-word Italian cohort: Evidence from the TG-RENAL Study.

BACKGROUND: This analysis investigated the role of hypertriglyceridemia on renal function decline and development of end-stage kidney disease (ESKD) in a real-world clinical setting. METHODS: A retrospective analysis using administrative databases of 3 Italian Local Health Units was performed searching patients with at least one plasma triglyceride (TG) measurement between 2013 and June 2020, followed-up until June 2021. Outcome measures included reduction in estimated glomerular filtration rate (eGFR) ≥30% from baseline and ESKD onset. Subjects with normal (normal-TG), high (HTG) and very high TG levels (vHTG) (respectively <150 mg/dL, 150-500 mg/dL and >500 mg/dL) were comparatively evaluated. RESULTS: Overall 45,000 subjects (39,935 normal-TGs, 5,029 HTG and 36 vHTG) with baseline eGFR of 96.0 ± 66.4 mL/min were considered. The incidence of eGFR reduction was 27.1 and 31.1 and 35.1 per 1000 person-years, in normal-TG, HTG and vHTG subjects, respectively (P<0.01). The incidence of ESKD was 0.7 and 0.9 per 1000 person-years, in normal-TG and HTG/vHTG subjects, respectively (P<0.01). Univariate and multivariate analyses revealed that HTG subjects had a risk of eGFR reduction or ESKD occurrence (composite endpoint) increased by 48% compared to normal-TG subjects (adjusted OR:1.485, 95%CI 1.300-1.696; P<0.001). Moreover, each 50 mg/dL increase in TG levels resulted in significantly greater risk of eGFR reduction (OR:1.062, 95%CI 1.039-1.086 P<0.001) and ESKD (OR:1.174, 95%CI 1.070-1.289, P = 0.001). CONCLUSIONS: This real-word analysis in a large cohort of individuals with low-to-moderate cardiovascular risk suggests that moderate-to-severe elevation of plasma TG levels is associated with a significantly increased risk of long-term kidney function deterioration.

Among biomarkers of neutrophil activity, matrix metalloproteinases 8 independently predicts remission of metabolic syndrome.

BACKGROUND AND AIMS: Inflammation due to the excess of nutrient intake plays an important role in the pathophysiology of metabolic syndrome (MetS). Here, the potential influence of neutrophils and their degranulation markers on MetS improvement upon dietary and behavioral counselling, has been investigated. Specifically, we aimed at investigating their role as potential predictors of metabolic syndrome improvements. METHODS AND RESULTS: patients with MetS (n = 127) received behavioral and dietary recommendations before follow-up at 6 months. Serum levels of matrix metalloproteinases (MMP)8, MMP9, myeloperoxidase (MPO), tissue inhibitor of MMP (TIMP)-1, TIMP-2, TIMP-3 and resistin were tested at baseline. In the whole cohort, baseline levels of proinflammatory MMP8, MMP9 and MPO increased together with the number of MetS criteria. Seventy-three (57%) patients experienced a reduction in MetS-defining criteria at follow-up. With respect to those with no improvement, such individuals showed lower weight and waist circumference at enrolment, less frequent smoking habits, higher levels of triglycerides and lower circulating MMP8. At logistic regression analysis, baseline MMP8 showed negative predictive ability (odds ratio (OR) 0.979 [0.961-0.997]; p = 0.025) against MetS improvement. Such findings hold true even when included in the backward stepwise logistic regression model confirming MMP8 as an independent predictor (OR 0.970 [0.949-0.993]; p = 0.009). Receiver operating characteristic (ROC) curve confirmed the predictive ability of MMP8 combined in a model including baseline MetS criteria and waist circumference. Bootstrap resampling analysis internally validated our findings. CONCLUSION: Improvement of MetS is independently associated with baseline low MMP-8 levels, suggesting a pivotal role for inflammation in metabolic alteration.

Impact of eGFR rate on 1-year all-cause mortality in patients with stable coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of mortality and is often complicated by chronic kidney disease. We sought to investigate the prevalence of different degree of estimated glomerular filtration rate (eGFR) reduction, the clinical and bio-humoral correlates, its relationship with therapeutic management, and its predictive role on 1-year all-cause mortality, in patients with stable CAD. METHODS: We studied 4,130 patients with stable CAD recruited in a prospective, observational, nationwide study (START, STable coronary Artery diseases RegisTry) in Italy. Baseline clinical characteristics, pharmacological treatment, and all-cause 1-year mortality were evaluated according to groups of eGFR (<30; 30-59; 60-89; ≥90 ml/min/1.73 m2) at baseline. RESULTS: The presence and the degree of chronic kidney disease entailed an unfavorable risk profile, since it was gradually associated with more comorbidities. Furthermore, progressively lower eGFR values were associated to lower diastolic blood pressure and hemoglobin values. As eGFR lowers, optimal medical treatment and its persistence overtime is reduced. Multivariate analysis showed that progressively lower eGFR significantly correlated with all-cause 1-year mortality [hazard ratio (HR): 1.02; 95% confidence intervals (CI): 1.01-1-03; p = 0.0001]. CONCLUSIONS: Low eGFR is associated with an increasing risk of all-cause mortality in patients with stable CAD. Chronic kidney disease may hamper the optimization of treatment limiting the use of drugs which may favorably impact cardiovascular and renal outcomes.

Renin-angiotensin-aldosterone system inhibition in patients affected by heart failure: efficacy, mechanistic effects and practical use of sacubitril/valsartan. Position Paper of the Italian Society of Cardiology.

Renin-angiotensin-aldosterone system (RAAS) inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). In the last years RAAS blockade has been improved by the introduction of the Angiotensin Receptor-Neprilysin Inhibitor (ARNI) sacubitril/valsartan, that combines RAAS inhibition with the block of neprilysin, boosting the positive effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a significant advantage of sacubitril/valsartan over enalapril on the reduction of cardiovascular (CV) mortality and heart failure hospitalizations rates. Then, several randomized clinical trials and observational studies investigated its role in different clinical settings and its efficacy has been fully recognized in the most recent HFrEF European and USA guidelines. The effects of sacubitril/valsartan on major CV outcomes are associated with reduction of NT-proBNP levels and reverse cardiac remodeling and mitral regurgitation, recognized as one of the mechanistic effects of the drug explaining the favorable prognostic effects. A careful evaluation of patients' clinical profile is relevant to implement the use of ARNI in the clinical practice and to obtain the maximal treatment efficacy. The present Position Paper reports the opinion of the Italian Society of Cardiology on the optimal blockade of the RAAS system in HF patients with the aim of fostering widespread implementation of scientific evidence and practice guidelines in the medical community.

SGLT-2 inhibitors for treatment of heart failure in patients with and without type 2 diabetes: A practical approach for routine clinical practice.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i), initially studied and approved for the treatment of diabetes, are now becoming a promising class of agents to treat heart failure (HF) and chronic kidney disease (CKD), even in patients without diabetes. While the potential benefits in several diseases (usually treated by different medical specialties) is amplifying the interest in these drugs, their use in frail patients with multiple pathologies and on polypharmacy can be complex, requiring a composite multidisciplinary approach. Following a brief overview of the evidence supporting the benefits of SGLT-2i in patients with HF or CKD, we herein provide guidance for prescribing SGLT-2i in daily practice using a multidisciplinary approach. A shared treatment algorithm is presented for initiating an SGLT-2i in patients already being treated for diabetes and HF. Tools to prevent hypoglycemia, blood pressure drop, genital infections, euglycemic diabetic ketoacidosis and eGFR dip are also provided. It is hoped that this practical, multidisciplinary guidance for initiating SGLT-2i in patients with HF and/or CKD, whatever therapy they are currently on, can help to offer SGLT-2i to the largest population of patients possible to provide the most therapeutic benefit.

Association of uric acid with kidney function and albuminuria: the Uric Acid Right for heArt Health (URRAH) Project.

BACKGROUND: Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). However, a better understanding of the relationship among uric acid (UA) values, glomerular filtration rate (GFR) and albuminuria may shed light on the mechanisms underlying the excess of cardiovascular mortality associated with both chronic kidney disease and hyperuricemia and lead to better risk stratification. Our main goal was to study the relationships between serum uric acid and kidney disease measures (namely estimated GFR [eGFR] and albuminuria) in a large cohort of individuals at cardiovascular risk from the URic acid Right for heArt Health (URRAH) Project database. METHODS: Clinical data of 26,971 individuals were analyzed. Factors associated with the presence of hyperuricemia defined on the basis of previously determined URRAH cutoffs for cardiovascular and all-cause mortality were evaluated through multivariate analysis. Chronic kidney disease was defined as eGFR < 60 ml/min per 1.73 m2 and/or abnormal urinary albumin excretion diagnosed as: (i) microalbuminuria if urinary albumin concentration was > 30 and ≤ 300 mg/L, or if urinary albumin-to-creatinine ratio (ACR) was > 3.4 mg/mmol and ≤ 34 mg/mmol; (ii) macroalbuminuria if urinary albumin concentration was > 300 mg/L, or if ACR was > 34 mg/mmol. RESULTS: Mean age was 58 ± 15 years (51% males, 62% with hypertension and 12% with diabetes), mean eGFR was 81 ml/min per 1.73m22with a prevalence of eGFR < 60 and micro- or macroalbuminuria of 16, 15 and 4%, respectively. Serum uric acid showed a trend towards higher values along with decreasing renal function. Both the prevalence of gout and the frequency of allopurinol use increased significantly with the reduction of eGFR and the increase in albuminuria. Hyperuricemia was independently related to male gender, eGFR strata, and signs of insulin resistance such as body mass index (BMI) and triglycerides. CONCLUSIONS: The lower the eGFR the higher the prevalence of hyperuricemia and gout. In subjects with eGFR < 60 ml/min the occurrence of hyperuricemia is about 10 times higher than in those with eGFR > 90 ml/min. The percentage of individuals treated with allopurinol was below 2% when GFR was above 60 ml/min, it increased to 20% in the presence of CKD 3b and rose further to 35% in individuals with macroalbuminuria.

Low eGFR and albuminuria independently predict all-cause mortality in high-risk subjects undergoing coronary arteriography.

Individuals with Chronic Kidney Disease (CKD) are at high risk for cardiovascular morbidity and mortality. The aim of this study was to examine the relationship between renal dysfunction and all-cause mortality in a sample of subjects undergoing coronary angiography (CA). We evaluated 1017 subjects who consecutively underwent CA. Glomerular filtration rate (eGFR) was estimated by CKD-EPI and urinary albumin excretion reported as urinary albumin-to-creatinine ratio. Vital status was ascertained by interrogating the Italian Health Card Database. One-thousand-seventeen subjects (759 M/258F) were enrolled into the study from 2016 to 2018. One-hundred-fourteen deaths occurred during a median follow-up of 44 months. The whole population was divided in two subgroups according to the presence/absence of low eGFR (i.e. < 60 ml/min/1.73 m2). Subjects with low baseline eGFR had a worse clinical profile than subjects with preserved kidney function. The risk of death in subjects with eGFR < 60 ml/min/1.73 m2 was almost three times higher than in subjects with preserved kidney function: fully adjusted HR 2.70 (95% CI 1.56-4.67). The presence of albuminuria also predicted a high risk of death: fully adjusted HR 2.09 (95% CI 1.17-3.73) and HR 4.26 (95% CI 2.18-8.33), microalbuminuria or macroalbuminuria, respectively, being normoalbuminuria the reference group. Again, the increased risk remained significant after adjusting for several potential confounders. In conclusion, kidney disease measures (i.e. low eGFR or albuminuria) independently predict increased risk for all-cause death in a large sample of subjects undergoing CA. These results have a relevant clinical impact.

Identification of a plausible serum uric acid cut-off value as prognostic marker of stroke: the Uric Acid Right for Heart Health (URRAH) study.

The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting combined (fatal and non-fatal) cerebrovascular (CBV) events in the whole database. The URic acid Right for heArt Health study is a nationwide, multicenter, observational cohort study involving data on subjects aged 18-95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 120.7 ± 61.8 months. A total of 14,588 subjects were included in the analysis. A prognostic cut-off value of SUA able to discriminate combined CBV events (>4.79 mg/dL or >284.91 µmol/L) was identified by means of receiver operating characteristic curve in the whole database. Multivariate Cox regression analysis adjusted for confounders (age, sex, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, body mass index, low-density lipoprotein cholesterol, and use of diuretics) identified an independent association between SUA and combined CBV events in the whole database (HR 1.249, 95% confidence interval, 1.041-1.497, p = 0.016). The results of the present study confirm that SUA is an independent risk marker for CBV events after adjusting for potential confounding variables, including arterial hypertension, and demonstrate that >4.79 mg/dL is a valid prognostic cut-off value.

Low GFR amplifies the association between coronary three-vessel disease and all-cause mortality.

BACKGROUND AND AIM: Three vessels disease (3VD) has been associated with worse prognosis and higher mortality. Chronic kidney disease (CKD) is an independent risk factor for premature death, mostly due to coronary artery disease (CAD). We aim to examine the prognostic impact of 3VD on all-cause mortality in a cohort of high cardiovascular risk subjects undergoing coronary angiography (CA) and to explore whether low eGFR (<60 ml/min/1.73 m2) modulates the risk of all-cause mortality associated to 3VD. METHODS AND RESULTS: One-thousand-seventeen subjects (759 M, mean age 68.4 ± 11 years) consecutive subjects undergoing CA from 2016 to 2018 were evaluated. Subjects were classified according to the severity of CAD as follows: group "three vessels disease" (3VD), and "no three vessels disease" (No 3VD). Serum creatinine was measured to estimate glomerular filtration rate (eGFR). The whole population was divided into 4 groups (A, B, C, D), according to the presence/absence of low eGFR and/or 3VD. One-hundred-fourteen deaths occurred (median follow-up:44 months). The risk of death in subjects with 3VD was almost 2-time higher than subject without 3VD (adjusted HR = 1.61; 95% CI 1.094-2.373, p = 0.0157). Among 4 subgroups, subjects with low eGFR and 3VD (Group D) had the highest risk of death (adjusted HR = 3.881; 95% CI 2.256-6.676, p < 0.0001). CONCLUSIONS: Low eGFR significantly amplifies the risk of all-cause mortality associated to 3VD. Our results strengthen the role of kidney disease as a risk multiplier for cardiovascular and all-cause mortality and highlight the need to prevent its onset and progression.

Clinical factors associated with death in 3044 COVID-19 patients managed in internal medicine wards in Italy: results from the SIMI-COVID-19 study of the Italian Society of Internal Medicine (SIMI).

During the COVID-19 2020 outbreak, a large body of data has been provided on general management and outcomes of hospitalized COVID-19 patients. Yet, relatively little is known on characteristics and outcome of patients managed in Internal Medicine Units (IMU). To address this gap, the Italian Society of Internal Medicine has conducted a nationwide cohort multicentre study on death outcome in adult COVID-19 patients admitted and managed in IMU. This study assessed 3044 COVID-19 patients at 41 referral hospitals across Italy from February 3rd to May 8th 2020. Demographics, comorbidities, organ dysfunction, treatment, and outcomes including death were assessed. During the study period, 697 patients (22.9%) were transferred to intensive care units, and 351 died in IMU (death rate 14.9%). At admission, factors independently associated with in-hospital mortality were age (OR 2.46, p = 0.000), productive cough (OR 2.04, p = 0.000), pre-existing chronic heart failure (OR 1.58, p = 0.017) and chronic obstructive pulmonary disease (OR 1.17, p = 0.048), the number of comorbidities (OR 1.34, p = 0.000) and polypharmacy (OR 1.20, p = 0.000). Of note, up to 40% of elderly patients did not report fever at admission. Decreasing PaO2/FiO2 ratio at admission was strongly inversely associated with survival. The use of conventional oxygen supplementation increased with the number of pre-existing comorbidities, but it did not associate with better survival in patients with PaO2/FiO2 ratio < 100. The latter, significantly benefited by the early use of non-invasive mechanical ventilation. Our study identified PaO2/FiO2 ratio at admission and comorbidity as the main alert signs to inform clinical decisions and resource allocation in non-critically ill COVID-19 patients admitted to IMU.

Serum uric acid, predicts heart failure in a large Italian cohort: search for a cut-off value the URic acid Right for heArt Health study.

OBJECTIVE: To assess the prognostic cut-off values of serum uric acid (SUA) in predicting fatal and morbid heart failure in a large Italian cohort in the frame of the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension. METHODS: The URic acid Right for heArt Health (URRAH) study is a nationwide, multicentre, cohort study involving data on individuals aged 18-95 years, recruited on a community basis from all regions of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 128 ±â€Š65 months. Incident heart failure was defined on the basis of International Classification of Diseases Tenth Revision codes and double-checked with general practitioners and hospital files. Multivariate Cox regression models having fatal and morbid heart failure as dependent variables, adjusted for sex, age, SBP, diabetes, estimated glomerular filtration rate, smoking habit, ethanol intake, BMI, haematocrit, LDL cholesterol, previous diagnosis of heart failure and use of diuretics as possible confounders, were used to search for an association between SUA as a continuous variable and heart failure. By means of receiver operating characteristic curves, two prognostic cut-off values (one for all heart failure and one for fatal heart failure) were identified as able to discriminate between individuals doomed to develop the event. These cut-off values were used as independent predictors to divide individuals according to prognostic cut-off values in a multivariate Cox models, adjusted for confounders. RESULTS: A total of 21 386 individuals were included in the analysis. In Cox analyses, SUA as a continuous variable was a significant predictor of all [hazard ratio 1.29 (1.23-1.359), P < 0.0001] and fatal [hazard ratio 1.268 (1.121-1.35), P < 0.0001] incident heart failure. Cut-off values of SUA able to discriminate all and fatal heart failure status were identified by mean of receiver operating characteristic curves in the whole database: SUA more than 5.34 mg/dl (confidence interval 4.37-5.6, sensitivity 52.32, specificity 63.96, P < 0.0001) was the univariate prognostic cut-off value for all heart failure, whereas SUA more than 4.89 mg/dl (confidence interval 4.78-5.78, sensitivity 68.29, specificity 49.11, P < 0.0001) for fatal heart failure. The cut-off for all heart failure and the cut-off value for fatal heart failure were accepted as independent predictors in the Cox analysis models, the hazard ratios being 1.645 (1.284-2.109, P < 0.0001) for all heart failure and 1.645 (1.284-2.109, P < 0.0001) for fatal heart failure, respectively. CONCLUSION: The results of the current study confirm that SUA is an independent risk factor for all heart failure and fatal heart failure, after adjusting for potential confounding variables and demonstrate that a prognostic cut-off value can be identified for all heart failure (>5.34 mg/dl) and for fatal heart failure (>4.89 mg/dl).

Long-term blood pressure behavior and progression to end-stage renal disease in patients with immunoglobulin A nephropathy: a single-center observational study in Italy.

BACKGROUND: Antihypertensive treatment by the use of RAAS inhibitors (RAAS-is) is of paramount importance in the management of slowly progressive IgA nephropathy (IgAN). With the aim of better understanding the relationship between BP behavior and progression, we looked at time-averaged SBP and time-averaged proteinuria and renal outcome in a single-center cohort of IgAN patients. METHODS: Among 248 consecutive patients referred to the Clinic of Nephrology of San Martino Hospital from 1996 to 2018 for native renal biopsy with a diagnosis of IgAN, we retrospectively analyzed 145 with available data at baseline and during follow-up. All patients received Supportive Care, 39% were on RAAS-is alone, 45% plus steroids, and 16% plus steroids and immunosuppressors. Renal replacing treatment (RRT) was the primary endpoint. RESULTS: During a mean follow-up of 67 ±â€Š6 months, 23% of study patients (n = 33) progressed to RRT and 6% (n = 9) died. Patients who reached the renal endpoint, had lower baseline eGFR and higher proteinuria and proteinuria indexed at baseline. Moreover, they had higher TA-SBP (139 ±â€Š17 vs. 130 ±â€Š13, P = 0.0016). The incidence of RRT was higher in IgAN patients in the highest time-averaged SBP tertile as compared with the others (32 vs. 23 vs. 9%, χ 6.8, P = 0.033). After adjusting for baseline SBP, baseline and time-averaged proteinuria indexed, MEST-C score, and treatment, the association between TA-SBP and RRT persisted. CONCLUSION: Time-averaged low BP values were independently associated to a decreased risk of renal progression in IgAN with no evidence of a J-curve relationship even at SBP levels below 125 mmHg.

Serum uric acid and fatal myocardial infarction: detection of prognostic cut-off values: The URRAH (Uric Acid Right for Heart Health) study.

OBJECTIVE: The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad-hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting fatal myocardial infaction (MI) in women and men. METHODS: The URic acid Right for heArt Health study is a nationwide, multicentre, observational cohort study involving data on individuals aged 18-95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 122.3 ±â€Š66.9 months. RESULTS: A total of 23 467 individuals were included in the analysis. Cut-off values of SUA able to discriminate MI status were identified by mean of receiver operating characteristic curves in the whole database (>5.70 mg/dl), in women (>5.26 mg/dl) and in men (>5.49 mg/dl). Multivariate Cox regression analyses adjusted for confounders (age, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, BMI, haematocrit, LDL cholesterol and use of diuretics) identified an independent association between SUA and fatal MI in the whole database (hazard ratio 1.381, 95% confidence intervals, 1.096-1.758, P = 0.006) and in women (hazard ratio 1.514, confidence intervals 1.105-2.075, P < 0.01), but not in men. CONCLUSION: The results of the current study confirm that SUA is an independent risk factor for fatal MI after adjusting for potential confounding variables, and demonstrate that a prognostic cut-off value associated to fatal MI can be identified at least in women.

Causes and impact on survival of underuse of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in heart failure.

Guidelines recommend angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) for treatment of heart failure with reduced ejection fraction (HFrEF), but these medications are underprescribed in clinical practice. We reviewed the records of HF patients receiving a first visit in a tertiary outpatient clinic from January 1st 2004 to May 31st 2015, and selected those with a serum creatinine concentration (sCr) available at both the first and last visit and < 3.5 mg/dL at baseline, and a left ventricular ejection fraction (LVEF) < 50% at the first visit. Of 570 eligible patients, 92 (16.1%) never received ACEi/ARB. Compared to ACEi/ARB users, never-users were older, more often women, had higher sCr and lower systolic blood pressure, were less commonly on beta-blocker, and had more frequently anemia. Current or prior cancer also tended to be more common in ACEi/ARB never-users. ACEi/ARB users displayed an improvement in LVEF by ≥ 10% of the baseline value more often than ACEi/ARB never-users (33.7% vs. 20.7%, respectively, P = 0.01), whereas no difference in percent variation of sCr levels was found between the two groups (8.2% vs. 3.1%, respectively; P = 0.13). Over a median follow-up of 56 months (range 1-137 months), 215 (37.7%) patients died. After multiple adjustments, ACEi/ARB never-use was associated with an almost twofold increased risk of all-cause mortality (HR 1.97, 95%CI 1.39-2.80). ACEi/ARB underuse in HFrEF is a standing issue with dramatic prognostic consequences. Efforts are needed to eliminate perceived contraindications to these drugs and ensure their implementation in real-life cardiology.

[ANMCO position paper on sacubitril/valsartan in the management of patients with heart failure]. / Position paper ANMCO sull'utilizzo della terapia con sacubitril/valsartan nel paziente con scompenso cardiaco.

Sacubitril/valsartan, the first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is the first medication to demonstrate a mortality benefit in patients with chronic heart failure and reduced ejection fraction (HFrEF) since the early 2000s. Sacubitril/valsartan simultaneously suppresses renin-angiotensin-aldosterone system activation through blockade of angiotensin II type 1 receptors and enhances the activity of vasoactive peptides including natriuretic peptides, through inhibition of neprilysin, the enzyme responsible for their degradation. In the landmark PARADIGM-HF trial, patients with HFrEF treated with sacubitril/valsartan had a 20% reduction in the primary composite endpoint of cardiovascular death or heart failure hospitalization, a 20% lower risk of cardiovascular death, a 21% to 20% lower risk of a first heart failure hospitalization, and a 16% to 20% lower risk of death from any cause, compared with subjects allocated to enalapril (all p<0.001).Following the trial, new international guidelines endorsed sacubitril/valsartan as a class I recommendation for the management of patients with HFrEF who remain symptomatic despite optimal medical management. In Italy, sacubitril/valsartan is reimbursed by the National Health Service since March 2017 within criteria set by the Italian Medicines Agency subject to patient inclusion in a dedicated monitoring registry. Although numerous post-hoc analyses of the original trial suggested that the benefits of this innovative medication may extend across a variety of subgroups, many questions do not yet have an evidence-based answer.In this position paper, we discuss the current role of sacubitril/valsartan in the management of chronic HFrEF, treatment eligibility and the modulating role of patients' characteristics. Moreover, we address concerns elicited by the PARADIGM-HF study and shortcomings of this novel drug, to clarify the place of this new therapy in the context of global care of heart failure in Italy. Our aim is to provide clinical cardiologists with a concise and practical guidance on when and how to use sacubitril/valsartan, to assist clinicians in closing the gap between scientific innovation and real-world experience.

Normoalbuminuric kidney impairment in patients with T1DM: insights from annals initiative.

BACKGROUND: We described, in a large sample of patients with type 1 diabetes mellitus (T1DM) and GFR ≤ 60 mL/min/1.73 m2 (with or without albuminuria), the differences in the clinical features associated with the two different chronic kidney disease phenotypes and we investigated, in a subset of patients, the modulating role of albuminuria on kidney disease progression. METHODS: Clinical data of 1395 patients with T1DM were extracted from electronic medical records. RESULTS: Albuminuria was detected in 676 (48.5%) patients, with the remaining 719 (51.5%) patients having normoalbuminuric renal impairment. Those with albuminuria showed an evident worse cardiovascular risk profile as compared to patients with normoalbuminuria. A subgroup of 582 patients was followed up over a 4-year period. One hundred and twenty five patients (21.5%) showed a loss of eGFR > 30%. The proportion of patients reaching the renal outcome was significantly higher among those with baseline albuminuria as compared to patients with normoalbuminuria (P < 0.0001). At the multivariate logistic analysis microalbuminuria, macroalbuminuria and proliferative retinopathy were the only parameters independently associated to eGFR reduction. CONCLUSIONS: The proportion of T1DM patients with normoalbuminuria renal impairment is high (about 50%). These patients have a slower eGFR decline as compared to that observed in patients with albuminuria renal impairment.

Diabetic kidney disease in the elderly: prevalence and clinical correlates.

BACKGROUND: Diabetic kidney disease (DKD) is a major burden in elderly patients with type 2 diabetes (T2DM). Low estimated glomerular filtration rate (eGFR+, < 60 mL/min/1.73 m2) and albuminuria (Alb+) are essential for the diagnosis of DKD, but their association with clinical variables and quality of care may be influenced by ageing. METHODS: Here we investigated the association of clinical variables and quality of care measures with eGFR+ and Alb+ in 157,595 T2DM individuals participating to the Italian Association of Clinical Diabetologists (AMD) Annals Initiative, stratified by age. RESULTS: The prevalence of eGFR+ and Alb+ increased with ageing, although this increment was more pronounced for low eGFR. Irrespective of age, both the eGFR+ and Alb + groups had the worst risk factors profile when compared to subjects without renal disease, showing a higher prevalence of out-of target values of HbA1c, BMI, triglycerides, HDL-C, blood pressure and more complex cardiovascular (CVD) and anti-diabetic therapies, including a larger use of insulin In all age groups, these associations differed according to the specific renal outcome examined: male sex and smoking were positively associated with Alb+ and negatively with eGFR+; age and anti-hypertensive therapies were more strongly associated with eGFR+, glucose control with Alb+, whereas BMI, and lipid-related variables with both abnormalities. All these associations were attenuated in the older (> 75 years) as compared to the younger groups (< 65 years; 65-75 years), and they were confirmed by multivariate analysis. Notably, Q-score values < 15, indicating a low quality of care, were strongly associated with Alb+ (OR 8.54; P < 0.001), but not with eGFR+. CONCLUSIONS: In T2DM patients, the prevalence of both eGFR and Albuminuria increase with age. DKD is associated with poor cardiovascular risk profile and a lower quality of care, although these associations are influenced by the type of renal abnormality and by ageing. These data indicate that clinical surveillance of DKD should not be unerestimated in old T2DM patients.

Cardiovascular risk and hypertension control in Italy. Data from the 2015 World Hypertension Day.

BACKGROUND: Cardiovascular diseases (CVD) are the first cause of death and disability in western countries. Despite therapeutic advances, their prevalence is constantly increasing. Detailed assessment of modifiable CV risk factors could improve CVD prevention and management. METHODS: to assess CV risk and hypertension control in a sample of the Italian population, individuals participating to the 2015 "World Hypertension Day" were interviewed in 62sites all over Italy. Blood pressure was measured with a validated auscultatory or oscillometric device and information on demography and prevalence of CVD risk factors was collected by an anonymous questionnaire. An ad-hoc modified version of the Systematic COronary Risk Evaluation (SCORE) system was then applied. RESULTS: 8657 recruited individuals (43%women, aged 56.68±16years) were subdivided into 3 age groups (40-49y, 50-59y, 60-69y) for analysis. CV risk was low in 62.4%, 18.0% and 0%; moderate in 26.0%, 66.0% and 62.5%; high/very high in 11.6%, 16% and 37.4%, respectively. Smoking was mainly responsible for increased CV risk among those aged 40-49y (26%smokers), while hypertension was the main factor in the whole sample and in subjects over 50y (36% and 42% respectively). Overall, BP control was unsatisfactory in 36% of individuals (28%, 48% and 31% of those who declared to be normotensive, hypertensive on treatment or unaware of their BP condition, respectively). CONCLUSIONS: In this sample of the Italian population, CV risk was alarmingly high, irrespectively of age, mostly due to presence of modifiable risk factors, including hypertension, which should thus be better addressed, especially in the youngsters.

Epidemiology of diabetic kidney disease in adult patients with type 1 diabetes in Italy: The AMD-Annals initiative.

BACKGROUND: Patients with type 1 diabetes mellitus are at increased risk of death. This risk appears to be modulated by kidney dysfunction. The aim of this study was to evaluate the prevalence of diabetic kidney disease (DKD), its traits, and clinical correlates in a large sample of patients with type 1 diabetes. METHODS: Clinical data of 20 464 patients with type 1 diabetes were extracted from electronic medical records. Estimated glomerular filtration rate (eGFR) and increased urinary albumin excretion were considered. RESULTS: Mean age of the patients was 46 ± 16 years, 55.0% were males, and duration of diabetes 19 ± 13 years. The frequency of diabetic kidney disease, low eGFR, and albuminuria was 23.5%, 8.1%, and 19.5%, respectively. In the multivariate analysis the presence of diabetic kidney disease was associated with age (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.10-1.18), duration of diabetes (OR = 1.05, 95% CI: 1.03-1.07), and worse glycemic control (OR = 1.24, 95% CI: 1.21-1.28, for every 1% glycated hemoglobin increase). Diabetic kidney disease was also independently associated with an atherogenic lipid profile and increased systolic blood pressure. Glucose control, systolic blood pressure, triglycerides, and high density lipoprotein cholesterol were associated with both low eGFR and albuminuria. Male gender, retinopathy and smoke were related to albuminuria, being female was related to low eGFR, while SUA levels were associated with DKD, low eGFR and albuminuria. CONCLUSIONS: In our sample of patients with type 1 diabetes, diabetic kidney disease entails an unsafe cardiovascular risk profile. Hyperglycemia, arterial hypertension, and atherogenic lipid profile affected both low eGFR and albuminuria. Retinopathy and smoking were related only to albuminuria while being female and elevated serum uric acid were associated only with low eGFR.