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Original Article Multicenter Prospective Observational Study on Acute and Chronic Heart Failure One-Year Follow-up Results of IN-HF (Italian Network on Heart Failure) Outcome Registry Luigi Tavazzi, MD; Michele Senni, MD; Marco Metra, MD; Marco Gorini, MS; Giuseppe Cacciatore, MD; Alessandra Chinaglia, MD; Andrea Di Lenarda, MD; Andrea Mortara, MD; Fabrizio Oliva, MD; Aldo P. Maggioni, MD; on the behalf of IN-HF (Italian Network on Heart Failure) Outcome Investigators* Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 Background—Clinical observational studies on heart failure (HF) deal mostly with hospitalized patients, few with chronic outpatients, all with no or limited longitudinal observation. Methods and Results—This is a multicenter, nationwide, prospective observational trial on a population of 5610 patients, 1855 hospitalized for acute HF (AHF) and 3755 outpatients with chronic HF (CHF), followed up for 1 year. The cumulative total mortality rate at 1 year was 24% in AHF (19.2% in 797 patients with de novo HF and 27.7% in 1058 with worsening HF) and 5.9% in CHF. Cardiovascular deaths accounted for 73.1% and 65.3% and HF deaths for 42.4% and 40.5% of total deaths in AHF and CHF patients, respectively. One-year hospitalization rates were 30.7% in AHF and 22.7% in CHF patients. Among the independent predictors of 1-year all-cause death, age, low systolic blood pressure, anemia, and renal dysfunction were identified in both acute and chronic patients. A few additional variables were significant only in AHF (signs of cerebral hypoperfusion, low serum sodium, chronic obstructive pulmonary disease, and acute pulmonary edema), whereas others were observed only in CHF patients (lower body mass index, higher heart rate, New York Heart Association class, large QRS, and severe mitral regurgitation). Conclusions—In this contemporary data set, patients with CHF had a relatively low mortality rate compared with those with AHF. Rates of adverse outcomes in patients admitted for AHF remain very high either in-hospital or after discharge. Most deaths were cardiovascular in origin and ≈40% of deaths were directly related to HF. (Circ Heart Fail. 2013;6:473-481.) Key Words: epidemiology ■ D heart failure ■ prognosis studies had a transversal design with no or limited longitudinal observation, and no previous registry included cohorts of patients with AHF and chronic HF (CHF) enrolled in the same setting. In Italy, through the series of the large cooperative GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico) randomized trials and nationwide observational studies, a vast experience on pragmatic clinical research has been achieved by cardiology centers, and an expert trial coordinating center has been developed. In consideration of the numerous limitations of available surveys and registries on HF mentioned above and the availability of an expert national clinical research structure, a nationwide registry was performed with the following main characteristics and uring the last decades, the interest in observational research by medical societies, health authorities, and drug or device companies has been rising for several reasons, including monitoring the incorporation of new diagnostic– therapeutic processes, and guidelines’ recommendations, need of awareness of met and unmet clinical needs, and use of the observational data as platform for continuous medical education and health authorities’ policy and strategy. Clinical Perspective on p 481 Several studies have been conducted in patients with heart failure (HF), particularly in those with acute HF (AHF), with rather inconsistent results.1–14 For instance, the in-hospital mortality rate ranged from <3%1 to >20%.5 Moreover, most Received July 16, 2012; accepted February 25, 2013. From the GVM Hospitals of Care and Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy (L.T.); USC Cardiovascular Medicine, Papa Giovanni XXIII Hospital, Bergamo, Italy (M.S.); Department of Cardiology, University and Spedali Civili, Brescia, Italy (M.M.); ANMCO Research Center, Florence, Italy (M.G., A.P.M.); Department of Cardiology, San Giovanni—Addolorata Hospital, Rome, Italy (G.C.); Cardiology Department, Maria Vittoria Hospital, Torino, Italy (A.C.); Cardiovascular Center, Azienda Servizi Sanitari n. 1 Triestina, Trieste, Italy (A.D.L.); Department of Clinical Cardiology and Heart Failure, Policlinico di Monza, Monza, Italy (A.M.); and Cardiologia 2-Heart Failure and Heart Transplant Program, “A. De Gasperis” Cardiovascular Department, Niguarda Hospital, Milan, Italy (F.O.). *A list of participating centers and investigators is given in the Appendix. Correspondence to Aldo P. Maggioni, MD, IN-HF Outcome Coordinating Center, ANMCO Research Center, Via La Marmora, 34 50121 Florence, Italy. E-mail [email protected] © 2013 American Heart Association, Inc. Circ Heart Fail is available at http://circheartfailure.ahajournals.org 473 DOI: 10.1161/CIRCHEARTFAILURE.112.000161 474 Circ Heart Fail May 2013 goals: (1) representativeness of the current HF population by implementing a network of enrolling centers of different complexity balanced with respect to the Italian hospital national network; (2) inclusion of both AHF and CHF patients in sizable samples, enrolled in the same centers; (3) systematic 1-year follow-up with a local monitoring to limit the number of lost to follow-up; and (4) investigation of clinical profiles, contemporary treatment, outcome rates, and their predictors in both AHF and CHF cohorts. Baseline characteristics and in-hospital findings of patients with AHF have been reported elsewhere.15 In the present study we have shown, and compared, the baseline characteristics and the 1-year outcomes of the AHF and CHF patients. Methods Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 This is a prospective, observational, nationwide study that involved 61 cardiology centers. The geographical distribution of hospitals across the country and the overall profile of the participating cardiology institutions were representative of the national setting of cardiovascular care in Italy. Enrollment could occur during a routine ambulatory visit (CHF patients) or at the time of admission to a cardiology ward (AHF patients). Patients’ enrollment lasted 2 years with a minimal follow-up of 1 year. Outpatient visits were performed at 3, 6, and 12 months after enrollment. Consecutiveness of enrollment was recommended but not checked with an admission log. There were no specific exclusion criteria, with the exception of age <18 years and patient unwillingness to participate. AHF patients were enrolled only if treated with intravenous therapy (diuretics, vasodilators, or inotropes). HF was classified as de novo HF in the absence of a history of HF and worsening HF if a previous diagnosis or hospitalization for HF was documented and a recent symptoms’ worsening was reported by the patient and confirmed by the physician. If not documented, a prior hospitalization was accepted as patient-reported. The patients were also classified according to the clinical categories suggested by the European Society of Cardiology guidelines.14 Patients were asked to sign an informed consent. Local Institutional Review Boards were informed of the study according to Italian national rules. Being the study observational, no specific protocols or recommendations for HF management were imposed. Current guidelines of HF,14 including the diagnostic criteria, were diffused and discussed during investigator meetings performed at the beginning of the study before starting patients’ enrollment. Participating doctors were invited to be adherent to them. Data were collected using a web-based system and stored in a central database. Statistical Analysis Categorical variables are presented as percentages, whereas continuous variables are presented as mean and SD if normally distributed, or as median and interquartile range, if not. Categorical variables were compared by the χ2 test and continuous variables by the t test or the Mann–Whitney U test. Plots of the Kaplan–Meier curves for time to all-cause death, time to admission to hospital for HF, and time to allcause death or HF hospitalization were performed. All the variables at entry which were statistically significant at univariate analysis and variables predefined as of relevant clinical interest were included in the multivariable model (Cox model) to identify the independent predictors of all-cause death from study entry to 1-year follow-up, separately for AHF and CHF. Age, systolic blood pressure (BP), heart rate, and body mass index were considered as continuous variables, whereas laboratory measures, not being available for all patients, were considered as categorical, using clinical cutoffs and defining a dummy variable for missing values. We considered as start point for the survival analyses the date of enrollment in the study. A P value of <0.05 was considered statistically significant. All tests were 2-sided. Analyses were performed with SAS system software, version 9.2. Figure 1. Patient disposition. AHF indicates acute heart failure; CHF, chronic heart failure; and pts, patients. Results From November 2007 to December 2009, 5610 patients were enrolled, 3755 were ambulatory patients with CHF and 1855 were patients admitted for AHF (797 with de novo HF and 1058 with worsening HF). One-year survival and hospitalizations’ data were available for 97.3% and 97.8% of patients with CHF and for 96.2% and 93.8% of patients with AHF, respectively (Figure 1). Seventy-nine percent of CHF patients and 78% of AHF patients had a 12-month follow-up clinical visit. In these patients data on therapy were recorded. Data on patients who died during the whole study period were not considered in these analyses. The clinical status at 12 months was ascertained by a telephone interview for patients not attending a clinical visit. Chronic Versus Acute (De Novo and Worsening) HF: Clinical Profiles at Enrollment Table 1 reports the characteristics of the study population. Patients with HF associated with an acute myocardial infarction were 239 (12.9%). AHF patients were older and more likely women than those with CHF. Mean values of systolic BP and heart rate as well as of body mass index were significantly higher in patients with AHF. The left ventricular ejection fraction was measured in 3804 patients, the mean value was identical in the 2 groups (38%) with a similar rate of patients with ejection fraction ≥40% (40.3% in CHF and 41.6% in AHF patients; P=0.44). Patients with AHF had a higher rate of comorbidities than CHF patients. Notably, these differences between acute and chronic patients were amplified when the subgroups with de novo and worsening HF were considered separately. The latter group showed a higher prevalence of comorbidities with more severe abnormalities of some biomarkers (hyponatremia, anemia, higher levels of blood urea nitrogen, and creatinine), whereas the former showed higher values of glycemia, heart rate, and systolic BP (Table 1). One-Year Outcomes Mortality and hospitalization rates in AHF and CHF during the follow-up are reported in Table 2 and Figure 2. Tavazzi et al Outcomes of Acute and Chronic Heart Failure 475 Table 1. Baseline Characteristics Chronic HF (n=3755) Age, y (mean±SD) Age ≥70 y, % Acute HF (n=1855) P Value* WHF (n=1058) DN-HF (n=797) P Value† 69±12 72±12 <0.0001 72±11 72±13 0.14 56 64 <0.0001 66 63 0.16 Women, % 24 40 <0.0001 37 43 0.01 Ischemic pathogenesis, % 46 42 0.02 45 38 0.003 27±4 28±5 <0.0001 28±6 28±5 0.32 22 29 <0.0001 29 29 0.78 126±19 134±33 <0.0001 129±30 141±34 <0.0001 14 20 <0.0001 24 15 <0.0001 70 [60–78] 90 [73–110] <0.0001 82 [70–100] 95 [80–116] <0.0001 38±11 38±14 0.87 37±14 39±14 0.007 Treated hypertension, % 43 58 <0.0001 56 61 0.03 Diabetes mellitus, % 30 40 <0.0001 43 37 0.008 BMI, kg/m2 (mean±SD) BMI ≥30 kg/m2, % SBP, mm Hg (mean±SD) SBP <110 mm Hg, % Heart rate, beats per minute (median [IQR]) LVEF, % (mean±SD) Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 COPD, % 21 30 <0.0001 33 27 0.003 Renal dysfunction, % 21 32 <0.0001 39 24 <0.0001 History of atrial fibrillation, % 30 38 <0.0001 43 30 <0.0001 5 5 0.91 5 5 0.89 Peripheral artery disease, % 13 20 <0.0001 22 18 0.01 ICD, % 19 9 <0.0001 15 2 <0.0001 Previous stroke, % CRT-D, % 7 4 <0.0001 6 1 <0.0001 CRT, % 2 2 0.60 2 1 0.005 Time from HF diagnosis >48 mo, % 54 52‡ 0.31 52 NA … Hospital admission for HF in the previous year, % 57 46‡ <0.0001 46 NA … Pulmonary congestion, % NA 78 … 76 81 0.004 Peripheral congestion, % NA 56 … 61 49 <0.0001 Pulmonary or peripheral congestion, % NA 88 … 88 89 0.40 Peripheral hypoperfusion, % NA 12 … 12 11 0.53 Cold, % NA 11 … 11 10 0.66 Somnolent, or confused, or sedated, % NA 12 … 10 14 0.003 13.3±1.7 12.5±2.1 <0.0001 12.3±2.0 12.9±2.1 <0.0001 20 39 <0.0001 44 32 <0.0001 Hemoglobin, g/dL (mean±SD) Hemoglobin <12 g/dL, % 1.2 [1.0–1.5] 1.2 [1.0–1.6] 0.11 1.3 [1.0–1.7] 1.1 [0.9–1.4] <0.0001 Creatinine >1.5 mg/dL, % Creatinine, mg/dL (median [IQR]) 22 29 <0.0001 34 22 <0.0001 eGFR <60 mL/min per 1.73 m2, % 48 55 <0.0001 61 46 <0.0001 eGFR <30 mL/min per 1.73 m2, % 6 13 <0.0001 15 10 0.001 Glycemia >126 mg/dL, % 27 57 <0.0001 53 61 0.001 Sodium <136 mEq/L, % 9 19 <0.0001 23 13 <0.0001 <0.0001 BUN >50 mg/dL, % NT-proBNP, pg/mL (median [IQR]) 53 58 0.03 65 48 1041 [475–2027] 5168 [2518–11583] <0.0001 4496 [2461–9492] 5964 [2680–13359] 0.14 BNP, pg/mL (median [IQR]) 372 [149–803] 1112 [542–2225] <0.0001 1200 [568–2314] 925 [540–2070] 0.37 hs-CRP, mg/L (median [IQR]) 2.6 [0.7–5.0] 7.0 [2.2–19.0] <0.0001 6.0 [1.5–14.9] 9.0 [3.3–23.1] 0.007 AHF indicates acute heart failure; BMI, body mass index; BNP, brain natriuretic peptide (available for 284 AHF patients and 59 CHF patients); BUN, blood urea nitrogen (available for 1411 AHF patients and 1341 CHF patients); CHF, chronic heart failure; COPD, chronic obstructive pulmonary disease; creatinine available for 1823 AHF patients and 2303 CHF patients; CRT, cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy defibrillator; DN-HF, de-novo heart failure; eGFR, estimaned glomerular filtration rate (available for 1823 AHF patients and 2303 CHF patients); glycemia available for 1733 AHF patients and 1452 CHF patients; hemoglobin available for 1828 AHF patients and 2235 CHF patients; HF, heart failure; hs-CRP, C reactive protein (available for 389 AHF patients and 81 CHF patients); ICD, implantable cardioverter defibrillator; IQR, interquartile range; LVEF, left ventricular ejection fraction (available for 1669 AHF patients and 2135 CHF patients); NA, not available; NT-proBNP, N-terminal proBNP (available for 274 AHF patients and 174 CHF patients); SBP, systolic blood pressure; sodium available for 1763 AHF patients and 1982 CHF patients; and WHF, worsening heart failure. *Comparison between CHF and AHF. †Comparison between WHF and DN-HF. ‡Evaluated on WHF patients. 476 Circ Heart Fail May 2013 Table 2. One-Year Outcomes Death All-cause death, % Chronic HF (n=3755) Acute HF (n=1855) P Value* <0.0001 5.9 24.0 Cause of death n=222 n=446 Unknown, % 18.5 11.0 Non-CV death, % 16.2 15.9 CV death, % 65.3 73.1 Heart failure, % 40.5 42.4 Myocardial infarction, % 3.6 Arrhythmias, % 9.9 Other CV causes, % 0.02 DN-HF (n=797) WHF (n=1058) P Value† <0.0001 19.2 27.7 n=153 n=293 6.5 13.3 18.3 14.7 75.2 72.0 37.3 45.1 10.5 15.0 8.2 6.7 7.8 6.1 0.02 0.08 0.09 11.3 13.5 15.0 12.6 Chronic HF (n=3755) Acute HF (n=1737‡) DN-HF (n=742‡) WHF (n=995‡) Patients admitted, % 22.7 30.7 <0.0001 22.1 37.1 <0.0001 Patients admitted for a CV reason, % 17.2 23.8 <0.0001 16.3 29.5 <0.0001 8.8 15.8 <0.0001 8.2 21.4 <0.0001 Hospitalization Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 Patients admitted for HF, % CV indicates cardiovascular; DN-HF, de novo heart failure; HF, heart failure; and WHF, worsening heart failure. *Comparison between chronic HF and acute HF. †Comparison between WHF and DN-HF. ‡Patients discharged alive. Patients With AHF Although all-cause mortality during hospital admission was similar in patients with de novo and worsening HF (6.9% vs 6.0%; P=0.41), the total mortality rate at 1 year was 24.0% overall, being, respectively, 19.2% and 27.7% (P<0.0001) in the 2 groups with AHF (Table 2; Figure 2A). Notably, among patients with de novo and worsening HF the postdischarge mortality rate constantly increased by 1% and 2% per month, respectively, up to 1 year. Cardiovascular deaths accounted for 73.1% of total deaths (whose 58% HF-related), noncardiovascular deaths for 15.9%, whereas an unknown cause was reported in 11.0% of AHF cases (Table 2). Among patients with AHF, the highest cumulative mortality rate was observed in patients with cardiogenic shock (38.1% at 1 year; mostly in-hospital, 23.8%), whereas the lowest mortality was observed in patients with an elevated systolic BP at the time of admission to hospital (15.8% at 1 year; mostly after discharge, 12.6%). Patients with AHF and concomitant acute coronary syndrome showed a high mortality rate, both in-hospital (13%) and after discharge (19.2%; Figure 3). All-cause rehospitalizations occurred in 30.7% of patients with AHF during the 1-year follow-up: for cardiovascular causes in 23.8% of patients (two third of them for HF), for noncardiovascular causes in 8.3%. Patients with worsening HF showed a higher readmission rate for HF (21.4%) than those with de novo HF (8.2%; Table 2; Figure 2B). The great majority of patients with AHF presented signs of peripheral or pulmonary congestion at the time of admission, whereas the rate of patients still showing some signs of congestion at discharge was 8.2%. During the follow-up, this turned out to be an ominous sign. The 1-year all-cause mortality of patients still congested at discharge was 37.1% versus 17.4% of those without congestion at discharge (P<0.0001). All-cause rehospitalization rate seemed to be less affected by this sign, being 37% versus 30%, respectively (P=0.08). Pharmacological treatments reported at discharge and at 1-year follow-up are presented in Figure 4A. Overall, the neurohormonal modulators’ prescriptions at discharge from hospital were maintained or improved afterward. The independent predictors of all-cause death at 1 year are reported in Table 3. Older age, high serum creatinine, high blood urea nitrogen, low serum sodium, chronic obstructive pulmonary disease, acute pulmonary edema, anemia, and symptoms of cerebral hypoperfusion were independently associated with a higher annual mortality rate. Higher systolic BP was an independent protective factor. Both heart rate, much higher in patients with worsening HF than in CHF patients (P<0.0001), and left ventricular ejection fraction did not emerge as independent predictors of events in the multivariable analysis. Biomarkers, such as brain natriuretic peptide and troponin, were measured at entry in a small number of patients and they could not be, therefore, included in the multivariable analyses. Ambulatory Patients With CHF The 1-year all-cause mortality of CHF patients was 5.9% (Figure 2A; Table 2), much higher in patients in New York Heart Association classes III and IV than in those in classes I and II (14.5% vs 4.1%; P<0.0001). Death rate was higher, but not significantly, in patients with an ischemic pathogenesis than in those with a nonischemic pathogenesis (6.5% vs 5.4%; P=0.17). Among the 222 patients with CHF who died at 1 year, 65.3% of deaths were because of cardiovascular reasons, and, among them, HF was the most frequent cause (62.1%) followed by arrhythmic deaths (15.2%). The 1-year admission rate was 22.7%, only one-third (8.8%) were because of HF. The proportion of HF hospitalizations was higher in patients with severe HF, whereas in patients with ischemic pathogenesis the prevalent cause of hospitalization was cardiovascular but not because of worsening HF. The rate of the use of pharmacological treatments was high at entry visit and did not change during the follow-up (Figure 4B). Tavazzi et al Outcomes of Acute and Chronic Heart Failure 477 Figure 3. Acute heart failure (HF) cohort. All-cause mortality by clinical profile at admission. ACS indicates acute coronary syndrome; CS, cardiogenic shock; PE, pulmonary edema; and RV, right ventricular. Discussion Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 We have compared the clinical characteristics and outcomes of 2 cohorts of patients, 1 of chronic stable HF outpatients and 1 of hospitalized HF patients with de novo or worsening HF. All patients of the 2 cohorts were enrolled in the same hospitals by the same investigators. Both cohorts have been followed up for 1 year being the survival status known at the end of follow-up in 97.3% and 96.2% of chronic and acute patients, respectively. AHF Patients Figure 2. Kaplan–Meier curves for all-cause death (A), admission to hospital for HF (B), and all-cause death or admission to hospital for HF (C). HF indicates heart failure. The variables independently associated with all-cause death at 1 year are shown in Table 4. Older age, higher heart rate, New York Heart Association class, anemia, larger QRS, high creatinine level, and the presence of severe mitral regurgitation were independently associated with a worse outcome, whereas higher systolic BP and higher body mass index resulted as independently associated with a lower mortality rate. As expected, the use of β-blockers was associated with a lower mortality, whereas the use of digitalis was with a higher one. This study confirms our previous findings11 of a significant difference between patients with de novo and worsening HF. Most comorbidities, including diabetes mellitus, chronic obstructive pulmonary disease, renal dysfunction, peripheral artery disease, atrial fibrillation, and anemia were much more frequent in the worsening HF group. Only renal dysfunction, chronic obstructive pulmonary disease, and anemia emerged as independent predictors of 1-year death at the multivariable analysis, but presumably the global burden of comorbidities influenced the event rates. For some of them, such as diabetes mellitus, 1-year follow-up may have been too short to assess their prognostic impact. Patients with de novo HF showed a high event rate during the first weeks after admission. Afterward, their clinical course was more stable with the all-cause death and HF hospitalization Kaplan–Meier curves showing an approximately parallel course as compared with that of CHF patients (Figure 2C) and the curve of HF hospitalization rate overlapping that of CHF (Figure 2B). Differently from patients with de novo HF, those hospitalized for worsening HF had much higher hospitalization and mortality rates during the year after discharge. This pattern is more impressive considering that both duration of HF (>48 months in 54% of patients with stable CHF and 52% of those with worsening AHF; P=0.31) and HF hospitalization rate in the previous year (57% and 46%, respectively; P<0.0001) were similar in both groups, showing the crucial role of abrupt worsening of symptoms in the natural history of HF.16 Among the variables analyzed as prognostic determinants at admission, those related to acute decompensation, such as water overload and neuro-hormonal activation (hyponatriemia and anemia), renal and circulatory dysfunction (high creatinine and blood urea nitrogen, cerebral hypoperfusion, 478 Circ Heart Fail May 2013 Figure 4. Pharmacological treatments at hospital discharge and 1 year of patients with acute heart failure (A), and at study entry and at the end of follow-up of patients with chronic heart failure (B). The analyses were performed only on patients with information on prescriptions available at baseline and at 1-year follow-up. ACE-I indicates angiotensin-converting enzyme-inhibitor; AldoB, aldosterone blockers; ARB, angiotensin II receptor blocker; and βB, beta blockers. Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 and acute pulmonary congestion),16 remained the most significant over the long term. Ejection fraction, available at hospital entry, did not result as a significant predictor of 1-year mortality even at univariate analysis. Persistence of congestion at the time of discharge affected a minority of patients (8%), probably because of the long duration of the hospitalization in Italy (median 10 days).15 However, it was strongly related to the 1-year outcome, with a 2-fold increase in the mortality rate. It is noteworthy that in these patients most late events were represented by death rather than by rehospitalization. These data are in agreement with recent analyses showing the predictive Table 3. Acute Heart Failure value of worsening signs of HF during the initial hospitalization in patients with AHF.17–19 Other observational studies investigated the outcome predictors in patients with AHF.6 However, most of them included observation periods limited to the hospital phase1,3,4,9,10,20 or ranging from 1 to 6 months after discharge.5–8,10 Most studies, including follow-up lasting 1-year or longer, were single center studies2,12 or multicenter studies focusing on very severe HF patients enrolled in general intensive care units.5 Table 4. Chronic Heart Failure Hazard Ratio 95% Confidence Interval P Value NYHA III–IV vs I–II 2.52 1.86–3.41 <0.0001 Hemoglobin <12 vs ≥12, g/dL 2.79 1.89–4.12 <0.0001 Age (per 5-year increase) 1.18 1.09–1.28 <0.0001 Hazard Ratio 95% Confidence Interval P Value Age (per 5-year increase) 1.20 1.14–1.27 <0.0001 HR (per 5-beats per minute increase) 1.09 1.04–1.15 0.0007 SBP (per 10-mm Hg increase) 0.90 0.86–0.93 <0.0001 Severe mitral regurgitation 2.03 1.31–3.15 0.002 Somnolent, confused, and sedated 2.03 1.58–2.62 <0.0001 β-Blockers 0.64 0.47–0.86 0.004 Sodium <136 vs ≥136, mEq/L 1.68 1.35–2.09 <0.0001 SBP (per 10-mm Hg increase) 0.90 0.83–0.98 0.012 Creatinine >1.5 vs ≤1.5, mg/dL 1.67 1.31–2.12 <0.0001 BMI (per 1-kg/m2 increase) 0.96 0.92–0.99 0.015 BUN >50 vs ≤50, mg/dL 1.84 1.37–2.46 <0.0001 QRS ≥120 vs <120, ms 1.47 1.08–2.02 0.015 Hemoglobin <12 vs ≥12, g/dL 1.49 1.21–1.83 0.0002 Digitalis 1.43 1.05–1.93 0.022 APE vs NYHA III–IV 1.32 1.05–1.66 0.017 Creatinine >1.5 vs ≤1.5, mg/dL 1.57 1.06–2.34 COPD 1.25 1.02–1.53 0.034 Independent predictors of all-cause 1-year mortality (ordered by χ2 value). The following variables were inserted in the Cox model: age, sex, SBP, heart rate, pathogenesis, COPD, history of renal dysfunction, previous stroke/ TIA, peripheral artery disease, clinical presentation, worsening or de novo, prior pace-maker, history of atrial fibrillation or atrial fibrillation at ECG, peripheral congestion, cognitive status, ejection fraction in the previous 6 mo, QRS duration, creatinine, sodium, hemoglobin, and BUN. APE indicates acute pulmonary edema; BUN, blood urea nitrogen; COPD, chronic obstructive pulmonary disease; HF, heart failure; NHYA, New York Heart Association; SBP, systolic blood pressure; and TIA, transient ischemic attack. 0.026 Independent predictors of all-cause 1-year mortality (ordered by χ value) The following variables were inserted in the Cox model (backward selection): age, sex, BMI, SBP, heart rate, duration of HF, HF hospitalization in the previous year, pathogenesis, diabetes mellitus, history of AF or AF at ECG, previous stroke/TIA, peripheral artery disease, chronic obstructive pulmonary disease, prior pace-maker, NYHA class, rales, sound 3, peripheral congestion, hemoglobin, creatinine, blood urea nitrogen, sodium, QRS, ejection fraction, severe mitral regurgitation, angiotensin-converting enzyme-inhibitor or angiotensin II receptor blocker, β-blockers, digitalis, aldosterone blockers. AF indicates atrial fibrillation; BMI, body mass index; HF, heart failure; HR, heart rate; NHYA, New York Heart Association; SBP, systolic blood pressure; and TIA, TIA, transient ischemic attack. 2 Tavazzi et al Outcomes of Acute and Chronic Heart Failure 479 The comprehensive and robust risk stratification models for in-hospital mortality from the Acute Decompensated Heart Failure National Registry (ADHERE) and Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) data bases3,6 did not include a long-term follow-up. One study published recently, dealing with AHF patients,20 included 1-year follow-up and gives similar results compared with those of the present study. This survey was conducted in 30 European countries and its main drawbacks are the limited representativeness of the participating countries and a rate of 13% patients lost to follow-up. In contrast, the main limitation of the present study is that of being a single country registry, with the advantages of a better compliance to follow-up and a good representativeness of the country’s cardiology network. At the end, the similarity of the findings of both studies reinforces each other. Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 CHF Patients Differently from the AHF domain, crowded by observational studies but poor of successful randomized controlled trials, in CHF domain large randomized controlled trials, mostly successful, have been performed,20–22 while few systematic observational studies have been reported. The present study shows 3 important findings. First, the recommended pharmacological treatments were incorporated into clinical practice and maintained over time. Second, the progressive nature of CHF looks relatively controlled with an annual mortality rate <6% (two third for cardiovascular causes). Third, several independent predictors of poor medium-term outcome have been identified. Among them, low systolic BP and low body weight are confirmed as alarming signals, together with severe mitral regurgitation, anemia, renal dysfunction, and a large QRS. High heart rate also emerged as an important marker of risk with a 2% increase in the probability of death within 1 year per 1 incremental heart beat. However, it is noteworthy that in our population, as in other studies,23,24 only 41% of deaths occurring during the follow-up were because of HF. Accordingly, in CHF, with advancing age, the concept of risk should be extended to a variety of comorbid conditions in a holistic view of the patients. The findings of the decreased risk associated with β-blocker treatment and the increased risk of digitalis therapy should be considered with great caution. In the daily practice, β-blockers are prescribed more frequently in patients with less severe HF,25 whereas digitalis is mostly given to patients resistant to other recommended therapy or in atrial fibrillation. Limitations Some important limitations of our survey must be acknowledged. First, although criteria for HF diagnosis were thoroughly discussed during the investigator meetings and the guidelines for HF diagnosis and treatment were commented on and distributed to all investigators, the diagnosis of HF remained at the discretion of the investigators based on their clinical judgment and without a central validation. Second, patients lost to follow-up were ≈3% for their vital status and ≈5% for their hospitalizations. This performance is suboptimal for a controlled study but in our view is acceptable for an observational study. Third, all enrolling centers were monitored with periodic visits by trained professionals of the coordinating center of the study, but a log of out- and inpatients admitted to the wards and clinics of the enrolling hospitals was not available. Accordingly, we cannot prove the consecutiveness of patients’ enrollment. Fourth, patients were enrolled in cardiology wards and clinics, not including those presenting at the emergency department, or admitted to other hospital facilities. Accordingly, the population reported in this article does not represent the universe of HF patients. Fifth, the ascertainment of cause of death was not adjudicated by a formal committee. Conclusions Although death rate of patients with CHF seems to slowly improve over time,26–28 outcomes’ rates of patients admitted for AHF are still very high in-hospital, and for several months after discharge. The in-hospital therapeutic approach to these patients has practically remained unchanged during the last decades and it is poorly effective. The therapeutic maintenance after discharge, able to control the disease progression in chronic phase, does not seem to work enough in the postacute phase. The outcomes’ predictors in both AHF and CHF in a representative Western country population have been defined. Appendix Steering Committee L. Tavazzi (Chairman), G. Cacciatore, A. Chinaglia, A. Di Lenarda, A.P. Maggioni, A. Mortara, M. Metra, F. Oliva, and M. Senni. Coordinating Center ANMCO (Italian Association of Hospital Cardiologists) Research Center (A.P. Maggioni, M. Gorini, I. Cangioli, L. Gonzini, D. Lucci, and L. Sarti). Participating Centers and Investigators Acerra (L. Ferrara); Albano Laziale (P. Midi, A. Felici, G. Pajes); Ancona (D. Gabrielli, A. Moraca); Aosta (G. Begliuomini, M. Sicuro); Ascoli Piceno (L. Moretti, G. Gregori); Benevento (D. Raucci, M. Scherillo); Bergamo, Ospedali Riuniti, U.C. Medicina Cardiovascolare (M. Gori, A. Fontana, M. Senni); Bergamo, Ospedali Riuniti, USC. Di Cardiologia (A. Grosu, A. Gavazzi); Brescia (R. Danesi); Bussolengo (A.M. Anselmi); Casarano (S. Ciricugno, C. Perrone, G. Piccinni); Castellammare Di Stabia (R. Longobardi); Catania (G. Arcidiacono, S. Felis); Conegliano (C. Marcon, P. Delise); Cosenza (G. Misuraca,F. Fascetti); Empoli (F. Venturi, A. Brandinelli Geri, A. Zipoli); Firenze, AOU Careggi (S. Valente, C. Giglioli, G. Gensini); Firenze, San Giovanni Di Dio (C. Minneci, G. Santoro); Garbagnate Milanese (F. Locati, S. Pardea); Legnano (C. Inserra, S. De Servi); Lumezzane (E. Zanelli, A. Giordano); Manduria (V. Russo); Merate (G. Lecchi, B. Riva, S. Maggiolini); Milano, Ospedale Niguarda, Cardiologia 2 (A. Verde, C. Vittori); Milano, Ospedale Niguarda, UO Attivita’ Ambulatorio Villa Marelli (E. Giagnoni, A. Sachero, A. Alberti); Milazzo (C. Coppolino, L. Vasquez); Montescano (G. Guazzotti, O. Febo); Monza, San Gerardo (A. Ciro’, A. Vincenzi, A. Grieco); Monza, Policlinico di Monza (A. Mortara, E. D’Elia); Napoli, AO Monaldi, Cardiologia Riabilitativa (D. Miceli); Napoli, AO Monaldi, UOC Cardiologia (S. Padula); Napoli, Incurabili (S. Luca’, N. Armogida); Orbassano (L. Montagna, G. Bonfiglio, R. Pozzi); Palermo, AOR Villa Sofia-Cervello PO Cervello (G. Celona, A. Floresta, A. Canonico); Palermo, AOR Villa SofiaCervello PO Villa Sofia (V. Cirrincione, F. Ingrilli’, N. Sanfilippo); Palmanova (R. Gortan, M. Baldin); Passirana-Rho (A. Frisinghelli, M. Veniani); Pavia (L. Scelsi, L. Oltrona Visconti); Pescia (G. Italiani, 480 Circ Heart Fail May 2013 W. Vergoni); Piedimonte Matese (L. De Risi, R. Battista); Poggibonsi (M. Romei); Pordenone (R. Piazza); Ravenna (G. Bellanti, G. Ricci Lucchi, M. Margheri); Reggio Calabria (G. Pulitano’, A. Ruggeri); Roma, AO San Giovanni Addolorata (G. Cacciatore, N. Pagnoni, A. Boccanelli); Roma, INRCA (D. Del Sindaco, M. Cangelosi); Roma, San Camillo (G. Pulignano, M. Pulcini, M. Fera); San Bonifacio (E. Carbonieri, M. Tinto, M. Anselmi); San Pietro Vernotico (A. Renna); Sarzana - Loc. S. Caterina (D. Bertoli, R. Petacchi); Sassari (F. Uras); Scorrano (O. De Donno, E. De Lorenzi); Siracusa (C. Rubera, E. Mossuti); Soriano Calabro (L. Anastasio); Teramo (L. Piccioni, C. Napoletano); Terni (M. Bernardinangeli, G. Proietti); Trieste (M. Merlo, M. Moretti, G. Sinagra); Vasto (G. Levantesi); Verbania (S. Randazzo); Veruno (A. Mezzani); and Vibo Valentia (L. Anastasio). Sources of Funding Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 The sponsor of the study was the Heart Care Foundation (Fondazione Italiana per la Lotta alle Malattie Cardiovascolari), a nonprofit independent institution which is also the owner of the database. Database management, quality control of the data, and data analyses were under the responsibility of the Research Center of the Italian Association of Hospital Cardiologists (ANMCO). The study was partially supported by an unrestricted grant by Novartis, Abbott, and Medtronic, Italy. No fees were provided to either cardiology centers or investigators. No compensation was provided to the members of the Steering Committee. The Steering Committee of the study had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. Disclosures Dr Tavazzi has received research grants from Boston Scientific and Vifor Pharma, has participated in speaker bureaus and advisory boards for Servier. Dr Metra has participated in speaker bureaus for Novartis and Servier, advisory boards for Novartis, Bayer and honoraria from Abbott Vascular, Bayer, Corthera, Novartis, and Servier. Marco Gorini is an employee of Heart Care Foundation, which conducted the study with an unresctricted grant of research from Novartis, Abbott, and Medtronic. Dr Maggioni is an employee of Heart Care Foundation, which conducted the study with an unresctricted grant from Novartis, Abbott, and Medtronic and has been a consultant for Novartis, Amgen, and Bayer. The other authors have no conflicts to report. References 1. O’Connor CM, Stough WG, Gallup DS, Hasselblad V, Gheorghiade M. Demographics, clinical characteristics, and outcomes of patients hospitalized for decompensated heart failure: observations from the IMPACTHF registry. J Card Fail. 2005;11:200–205. 2.Rudiger A, Harjola VP, Müller A, Mattila E, Säila P, Nieminen M, Follath F. Acute heart failure: clinical presentation, one-year mortality and prognostic factors. Eur J Heart Fail. 2005;7:662–670. 3. 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Senni M, De Maria R, Gregori D, Gonzini L, Gorini M, Cacciatore G, Gavazzi A, Pulignano G, Porcu M, Maggioni AP. Temporal trends in survival and hospitalizations in outpatients with chronic systolic heart failure in 1995 and 1999. J Card Fail. 2005;11:270–278. Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 CLINICAL PERSPECTIVE In consideration of the limitations of available surveys and registries of heart failure (HF) patients, a nationwide registry was performed with the aim to include both acute and chronic heart failure patients, representative of the current HF population complexity balanced with respect to the Italian hospital population samples. From November 2007 to December 2009, 5610 HF patients were enrolled, 3755 were ambulatory patients with chronic heart failure and 1855 were patients admitted for acute heart failure (797 with de novo HF and 1058 with worsening HF). Although the death rate of patients with chronic heart failure slowly diminished over time, the adverse outcome rates of patients admitted for acute heart failure were still very high in-hospital, and also for several months after discharge. The in-hospital therapeutic approach to these patients has remained essentially unchanged during the last decades, in contrast to the advances for those with chronic heart failure. The still unacceptably high rate of death of patients hospitalized for acute heart failure clearly calls for therapeutic progress in that area. The therapeutic maintenance or optimization of evidence-based treatments after discharge, effective in controlling disease progression and favorably impacting the outcome of patients with chronic heart failure, does not seem to be as effective in the postacute heart failure phase. Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 3, 2017 Multicenter Prospective Observational Study on Acute and Chronic Heart Failure: One-Year Follow-up Results of IN-HF (Italian Network on Heart Failure) Outcome Registry Luigi Tavazzi, Michele Senni, Marco Metra, Marco Gorini, Giuseppe Cacciatore, Alessandra Chinaglia, Andrea Di Lenarda, Andrea Mortara, Fabrizio Oliva and Aldo P. Maggioni Circ Heart Fail. 2013;6:473-481; originally published online March 8, 2013; doi: 10.1161/CIRCHEARTFAILURE.112.000161 Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-3289. 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