Franco Cosmi

Clinical outcome of renal tubular damage in chronic heart failure

AIMS Both reduced glomerular filtration and increased urinary albumin excretion independently determine outcome in patients with chronic heart failure (HF). However, tubulo-interstitial injury might indicate renal damage, even in the presence of normal glomerular filtration. We studied the relationship between tubular damage, glomerular filtration, urinary albumin excretion, and outcome in HF patients. METHODS AND RESULTS In 2130 patients participating in the GISSI-HF trial, we measured urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and three urinary markers of tubular damage: N-acetyl-beta-D-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). We assessed the relationship between the individual tubular damage markers and the combined endpoint of all-cause mortality and HF hospitalizations. Mean age was 67 ± 11 years, and 21% were female. Urinary NAG 13.7 (7.8-22) U/gCr, KIM-1 1939 (671-3871) ng/gCr, and NGAL 36 (14-94) µg/gCr were markedly elevated above normal levels. All individual tubular markers were independently associated with the combined endpoint: NAG: adjusted hazard ratio (HR) 1.22; 95% confidence interval (CI), 1.10-1.36; P< 0.001, KIM-1 HR 1.13; 95% CI, 1.02-1.24; P= 0.018 and NGAL HR 1.10; 95% CI, 1.00-1.20; P= 0.042; all per log standard deviation increase). Even in patients with a normal eGFR, increased tubular markers were related to a poorer outcome. The combination of impaired eGFR, increased UACR, and high NAG was associated with a HR of 3.00; 95% CI, 2.29-3.95; P< 0.001, compared with those without these abnormalities. CONCLUSION Tubular damage is related to a poor clinical outcome in HF patients even when eGFR is normal.

Effects of rosuvastatin on atrial fibrillation occurrence: ancillary results of the GISSI-HF trial

AIMS This ancillary analysis of the GISSI-HF database aims at assessing the effect of rosuvastatin on the occurrence of atrial fibrillation (AF) in patients with chronic heart failure (HF) who were not in AF at study entry. METHODS AND RESULTS GISSI-HF was a double-blind, placebo-controlled trial testing n-3 PUFA and rosuvastatin vs. corresponding placebos in patients with chronic HF. Atrial fibrillation occurrence was defined as the presence of AF in the electrocardiogram (ECG) performed at each visit during the trial or AF as a cause of worsening HF or hospital admission or as an event during hospitalization. Among the 3690 patients (80.7%) without AF on their baseline ECG, 15.0% developed AF during a median follow-up period of 3.7 years, 258 randomized to rosuvastatin (13.9%) vs. 294 allocated to placebo (16.0%). Although the difference was not significant at unadjusted analysis (P = 0.097) and multivariable analysis adjusting for clinical variables (P = 0.067), it became significant after adjustment for clinical variables and laboratory examinations (P = 0.039), and for clinical variables, laboratory examinations, and background therapies (P = 0.038). CONCLUSION This study shows that there is some evidence of a beneficial effect of rosuvastatin in terms of reduction of AF occurrence in patients with HF. Larger populations are needed to provide a definite answer to the question. ClinicalTrials.gov Identifier: NCT00336336.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%).

Thromboembolic event rate in paroxysmal and persistent atrial fibrillation: Data from the GISSI-AF trial

BackgroundFew data on the thromboembolic (TE) risk of paroxysmal and persistent atrial fibrillation (AF) are available. This study aimed to assess the incidence of TE events in paroxysmal and persistent AF.MethodsWe performed a subset post hoc analysis of 771 patients with paroxysmal and 463 with persistent AF enrolled in the multicenter, prospective, randomized, double-blind, placebo-controlled GISSI-AF trial - comparing the efficacy of valsartan versus placebo in preventing AF recurrences – where the choice of antithrombotic treatment was left to the judgment of the referring physician. TE and major outcome events were centrally validated. AF recurrences were detected by frequent clinic visits and a transtelephonic monitoring device with weekly and symptomatic transmissions.ResultsEighty-five percent of patients had a history of hypertension, and the 7.7% had heart failure, left ventricular dysfunction, or both. The mean CHADS2 score was 1.41±0.84. TE and major bleeding events were observed at a low incidence among the overall population at 1-year follow-up (0.97% and 0.81%, respectively). The univariate and multivariable analyses revealed no statistically significant differences in the incidence of TE, major bleeding events or mortality in paroxysmal and persistent AF patients. TE events were more common among women than men (p=0.02). The follow-up examination showed under- or overtreatment with warfarin in many patients, according to guideline suggestions. Warfarin was more frequently prescribed to patients with persistent AF (p<0.0001) and patients with AF recurrences (p<0.0001). AF recurrences were noninvasively detected in 632 (51.2%) patients. In patients without AF recurrences, the TE event rate was 0.5% versus 1.74%, 1.28%, and 1.18% for those with only symptomatic, only asymptomatic or both symptomatic and asymptomatic AF recurrences, respectively, but the difference was not statistically significant, even after adjusting for warfarin treatment and the CHADS2 score (HR 2.93; CI 95%; 0.8-10.9; p=0.11).ConclusionsTE and major bleeding events showed a very low incidence in the GISSI-AF trial population, despite under- or overtreatment with warfarin in many patients. TE events had a similar rate in paroxysmal and persistent AF.Trial registrationTrial registration number: NCT00376272

Clinical predictors of atrial fibrillation recurrence in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial

BACKGROUND Atrial fibrillation (AF) is a common arrhythmia that frequently recurs after restoration of sinus rhythm (SR). Identifying risk factors for recurrence may help define the best strategy for secondary prevention. METHODS The GISSI-AF trial enrolled 1,442 patients in SR with at least 2 documented AF episodes in the previous 6 months or after cardioversion in the last 2 weeks. Patients were randomized to valsartan or placebo; all other treatments for AF or underlying heart diseases were allowed. Primary end points were time to first recurrence of AF and proportion of patients with >1 AF episode during 1-year follow-up. We evaluated clinical and electrocardiographic baseline characteristics of all patients to identify independent predictors for AF recurrence using a Cox multivariable model. RESULTS Risk factors for AF recurrence were a history of 2 or more AF episodes in the previous 6 months, independent of the modality of SR restoration, spontaneous (HR 1.42, 95% CI 1.14-1.77, P = .002), or by cardioversion (HR 1.19, 95% CI 1.01-1.40, P = .038), and a lower heart rate during SR (HR 0.99, 95% CI 0.99-1.00, P = .052). The risk factors were the same for >1 AF recurrence. Patients treated with amiodarone had a lower risk for both end points (P < .0001 and P = .017), whereas those on diuretics had a greater risk (P = .009 and P = .003). CONCLUSIONS In the GISSI-AF study population, AF history had significant prognostic value independent of the modality of SR restoration. Amiodarone and diuretic treatment affected the rate of AF recurrence.

Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes

Up to one‐third of patients with diabetes mellitus and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse outcomes.

Prognostic impact of diabetes and prediabetes on survival outcomes in patients with chronic heart failure: A post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial

Background The independent prognostic impact of diabetes mellitus (DM) and prediabetes mellitus (pre‐DM) on survival outcomes in patients with chronic heart failure has been investigated in observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre‐DM on survival outcomes in the GISSI‐HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure) trial. Methods and Results We assessed the risk of all‐cause death and the composite of all‐cause death or cardiovascular hospitalization over a median follow‐up period of 3.9 years among the 6935 chronic heart failure participants of the GISSI‐HF trial, who were stratified by presence of DM (n=2852), pre‐DM (n=2013), and non‐DM (n=2070) at baseline. Compared with non‐DM patients, those with DM had remarkably higher incidence rates of all‐cause death (34.5% versus 24.6%) and the composite end point (63.6% versus 54.7%). Conversely, both event rates were similar between non‐DM patients and those with pre‐DM. Cox regression analysis showed that DM, but not pre‐DM, was associated with an increased risk of all‐cause death (adjusted hazard ratio, 1.43; 95% CI, 1.28–1.60) and of the composite end point (adjusted hazard ratio, 1.23; 95% CI, 1.13–1.32), independently of established risk factors. In the DM subgroup, higher hemoglobin A1c was also independently associated with increased risk of both study outcomes (all‐cause death: adjusted hazard ratio, 1.21; 95% CI, 1.02–1.43; and composite end point: adjusted hazard ratio, 1.14; 95% CI, 1.01–1.29, respectively). Conclusions Presence of DM was independently associated with poor long‐term survival outcomes in patients with chronic heart failure. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336.

Regular Wine Consumption in Chronic Heart Failure: Impact on Outcomes, Quality of Life, and Circulating Biomarkers

Background— Moderate, regular alcohol consumption is generally associated with a lower risk of cardiovascular events but data in patients with chronic heart failure are scarce. We evaluated the relations between wine consumption, health status, circulating biomarkers, and clinical outcomes in a large Italian population of patients with chronic heart failure enrolled in a multicenter clinical trial. Methods and Results— A brief questionnaire on dietary habits was administered at baseline to 6973 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial. The relations between wine consumption, fatal and nonfatal clinical end points, quality of life, symptoms of depression, and circulating biomarkers of cardiac function and inflammation (in subsets of patients) were evaluated with simple and multivariable-adjusted statistical models. Almost 56% of the patients reported drinking at least 1 glass of wine per day. After adjustment, clinical outcomes were not significantly different in the predefined 4 groups of wine consumption. However, patients with more frequent wine consumption had a significantly better perception of health status (Kansas City Cardiomyopathy Questionnaire score, adjusted P <0.0001), less frequent symptoms of depression (Geriatric Depression Scale, adjusted P =0.01), and lower plasma levels of biomarkers of vascular inflammation (osteoprotegerin and C-terminal proendothelin-1, adjusted P <0.0001, and pentraxin-3, P =0.01) after adjusting for possible confounders. Conclusions— We show for the first time in a large cohort of patients with chronic heart failure that moderate wine consumption is associated with a better perceived and objective health status, lower prevalence of depression, and less vascular inflammation, but does not translate into more favorable clinical 4-year outcomes. Clinical Trial Registration— URL: . Unique identifier: NCT0033633.Background—Moderate, regular alcohol consumption is generally associated with a lower risk of cardiovascular events but data in patients with chronic heart failure are scarce. We evaluated the relations between wine consumption, health status, circulating biomarkers, and clinical outcomes in a large Italian population of patients with chronic heart failure enrolled in a multicenter clinical trial. Methods and Results—A brief questionnaire on dietary habits was administered at baseline to 6973 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial. The relations between wine consumption, fatal and nonfatal clinical end points, quality of life, symptoms of depression, and circulating biomarkers of cardiac function and inflammation (in subsets of patients) were evaluated with simple and multivariable-adjusted statistical models. Almost 56% of the patients reported drinking at least 1 glass of wine per day. After adjustment, clinical outcomes were not significantly different in the predefined 4 groups of wine consumption. However, patients with more frequent wine consumption had a significantly better perception of health status (Kansas City Cardiomyopathy Questionnaire score, adjusted P<0.0001), less frequent symptoms of depression (Geriatric Depression Scale, adjusted P=0.01), and lower plasma levels of biomarkers of vascular inflammation (osteoprotegerin and C-terminal proendothelin-1, adjusted P<0.0001, and pentraxin-3, P=0.01) after adjusting for possible confounders. Conclusions—We show for the first time in a large cohort of patients with chronic heart failure that moderate wine consumption is associated with a better perceived and objective health status, lower prevalence of depression, and less vascular inflammation, but does not translate into more favorable clinical 4-year outcomes. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT0033633.

[Metformin and insulin in chronic heart failure: contraindications not contraindicated and indications not indicated].

Glucose-lowering treatment in patients with type 2 diabetes and heart failure is controversial. Metformin is clearly contraindicated when such diseases coexist. Conversely, no contraindications have been established for insulin in this subset of patients, even though several observational and retrospective studies have shown increased mortality and worsening heart failure. Data from the literature have demonstrated that in this patient population, which accounts for one third of all cases of heart failure, metformin reduces mortality by 14-35%. In patients with a glomerular filtration rate >30 ml/min who do not show dehydration, shock, sepsis, severe liver disease or hypoxemia, the administration of metformin doses <2 g/day was associated with a null risk of lactic acidosis. The positive effects of metformin are correlated with the reduction in insulin resistance, which is responsible for both the onset and development of heart failure in diabetic patients. Insulin can provoke severe hypoglycemia and fluid retention, resulting in negative effects. Further randomized and prospective studies are warranted to address these controversial issues in such a large population with high mortality and morbidity rates. Longitudinal studies would be crucial to the understanding of the optimal therapy and for stratification of patients according to the severity of heart failure.

Prognostic impact of elevated serum uric acid levels on long-term outcomes in patients with chronic heart failure: A post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial

BACKGROUND The prognostic impact of hyperuricemia on long-term clinical outcomes in patients with chronic heart failure (HF) has been investigated in observational registries and clinical trials, but the results have been often inconclusive. We examined the prognostic impact of elevated serum uric acid levels on long-term clinical outcomes in the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial. CLINICAL TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER NCT00336336. METHODS We assessed the rates of all-cause death, cardiovascular death, cardiovascular hospitalization and the composite of all-cause death or cardiovascular hospitalization over a median follow-up of 3.9 years among 6683 ambulatory patients with chronic HF. RESULTS Patients in the 3rd serum uric acid tertile (>7.2 mg/dl) had a nearly 1.8-fold increased risk of both all-cause death and cardiovascular death, and a nearly 1.5-fold increased risk of cardiovascular hospitalization and of the composite endpoint compared to those in the 1st uric acid tertile (<5.7 mg/dl). Beyond serum uric acid ≥ 7 mg/dl the risk of outcomes increased sharply and linearly. The significant association between elevated serum uric acid levels and adverse outcomes persisted after adjustment for multiple established cardiovascular risk factors, HF etiology, left ventricular ejection fraction, medication use and other potential confounders, with an adjusted hazard ratio of 1.37 (95% CI 1.22-1.55) for all-cause death, 1.48 (1.29-1.69) for cardiovascular death, 1.19 (1.09-1.30) for cardiovascular hospitalization and 1.21 (1.11-1.31) for the composite endpoint, respectively. CONCLUSIONS Elevated serum uric acid levels are independently associated with poor long-term survival and increased risk of cardiovascular hospitalization in patients with chronic HF.