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Treatment With Inotropes And Related Prognosis In Acute Heart Failure: Contemporary Data From The Registry In-Hf Outcome Andrea Mortara MD, Fabrizio Oliva MD, Marco Metra MD, Emanuele Carbonieri MD, Andrea Di Lenarda MD, Marco Gorini MS, Paolo Midi MD, Michele Senni MD, Renato Urso MS, Donata Lucci MS, Aldo P. Maggioni MD, Luigi Tavazzi MD, on the behalf of the IN HF Outcome Investigators

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S1053-2498(14)01152-8 http://dx.doi.org/10.1016/j.healun.2014.05.015 HEALUN5785

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J Heart Lung Transplant

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Cite this article as: Andrea Mortara MD, Fabrizio Oliva MD, Marco Metra MD, Emanuele Carbonieri MD, Andrea Di Lenarda MD, Marco Gorini MS, Paolo Midi MD, Michele Senni MD, Renato Urso MS, Donata Lucci MS, Aldo P. Maggioni MD, Luigi Tavazzi MD, on the behalf of the IN HF Outcome Investigators, Treatment With Inotropes And Related Prognosis In Acute Heart Failure: Contemporary Data From The Registry In-Hf Outcome, J Heart Lung Transplant, http://dx.doi.org/10.1016/j. healun.2014.05.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

TREATMENT WITH INOTROPES AND RELATED PROGNOSIS IN ACUTE HEART FAILURE: CONTEMPORARY DATA FROM THE REGISTRY IN-HF OUTCOME Andrea Mortara1, MD, Fabrizio Oliva2, MD, Marco Metra3, MD, Emanuele Carbonieri4, MD, Andrea Di Lenarda5, MD, Marco Gorini6, MS, Paolo Midi7, MD, Michele Senni8, MD, Renato Urso6, MS, Donata Lucci6, MS, Aldo P. Maggioni6, MD, Luigi Tavazzi9, MD on the behalf of the IN HF Outcome Investigators 1

Dept. of Clinical Cardiology and Heart Failure, Policlinico di Monza, Monza; 2Cardiologia 2 Heart

Failure and Heart Transplant Program, “A. De Gasperis” Cardiovascular Dept., Niguarda Hospital, Milano; 3Cardiology, University and Spedali Civili of Brescia, Brescia; 4Cardiology Dept., Orlandi Hospital, Bussolengo; 5Cardiovascular Unit, Azienda Servizi Sanitari n. 1 Triestina, Trieste; 6ANMCO Research Center, Firenze; 7Cardiology Dept., Ospedali Riuniti Albano-Genzano, Albano Laziale; 8USC Cardiovascular Medicine, Papa Giovanni XXIII Hospital, Bergamo; 9Maria Cecilia Hospital - GVM Care&Research - E.S. Health Science Foundation, Cotignola, Italy Short title: INOTROPES AND ACUTE HEART FAILURE Word count: 3.261 (text plus abstract) Key words: Acute heart failure; Inotropes; Treatment; Prognosis; Registry. Address for correspondence: Aldo P. Maggioni, IN-HF Outcome Coordinating Center, ANMCO Research Center, Via La Marmora, 34 – 50121 Firenze, Italy – Phone +39-055-5101361 – Fax +39-0555101310, e-mail: [email protected] Funding: The study was partially supported by an unrestricted grant by Novartis, Abbott and Medtronic, Italy. The sponsor of the study was Heart Care Foundation, a non-profit independent institution which is also the owner of the database. Database management and quality control of the data were under the responsibility of the research centre of the Italian Association of Hospital Cardiologists (ANMCO). No fees were provided to either cardiology centres or investigators. ABSTRACT Background: In a recent Italian registry (IN-HF Outcome) including 1855 patients with acute heart failure (AHF), we have reviewed the use of inotropes and their prognostic implication on in-hospital and 12-month mortality. Methods and results: IN-HF Outcome is a prospective, multicenter, observational, study involving 61

Italian Cardiology centers. AHF patients have been enrolled over 2 years and followed-up for 1 year. Inotropes were used in 360 patients (19.4%). Patients receiving inotropes had a more severe clinical and hemodynamic profile than those who did not and exhibited a significantly higher in hospital (21.4 vs 2.7%, p110 mmHg, despite a more favorable clinical profile, exhibited a similar worse prognosis particularly at 1 year: 56.3% (≤110 mmHg), 43.7% (111-130 mmHg) and 40.3% (>130 mmHg) vs 17.7%. Conclusions: Inotropes were used in nearly 20% of the patient admitted for AHF and this treatment was associated with a short-medium term poor prognosis. An inappropriate use in those patients with normal to high SBP, and presumably preserved cardiac output, may have significantly contributed to affect all group outcome. INTRODUCTION Acute heart failure (AHF) is the most common and morbid acute cardiovascular condition in the West.[1] Fluid overload and pulmonary congestion with elevated LV end-diastolic pressure and pulmonary wedge pressure are the main indications for hospitalization.[2-3] Approximately 10% of all patients admitted for AHF have low blood pressure (BP), signs of end-organ dysfunction, and severe left ventricular (LV) systolic and diastolic dysfunction.[3] Administration of inotropic agents is potentially the only medical treatment that can improve hemodynamic abnormalities and symptoms.[4] Unfortunately, most inotropic agents are associated with untoward effects on outcomes. The European Society of Cardiology guidelines state that inotropic agents are indicated only for patients with low systolic BP (SBP) or a low measured cardiac index in the presence of signs of peripheral hypoperfusion or congestion.[3] These indications are in agreement with the current guidelines of the American College of Cardiology/American Heart Association[5] and Heart Failure Society of America.[6] However, data from registries show wide variation in the proportion of patients treated with inotropes: 7%

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in the OPTIMIZE-HF study,[7] nearly 25% in the EHFS-II study,[8] and 0.9–45% in a recent registry of US hospitals.[9] The use of inotropic agents is consistently not based on current guidelines and has been repeatedly shown to be one of the most powerful independent predictors of death.[10, 11] We recently published results concerning the in-hospital management and outcomes of patients with AHF enrolled in the “IN-HF Outcome” registry, a nationwide, multicenter, observational study conducted in Italian cardiology centers.[12, 13]. The purpose of the present study is to describe the current use of inotropic drugs and to assess its possible prognostic impact. STUDY DESIGN AND METHODS IN-HF Outcome involved 61 Italian cardiology centers well distributed throughout the entire country. Patients were enrolled during a 2-year period (from 23 November 2007 to 31 December 2009) and were followed for 1 year. Data were collected in a central database using a web connection. AHF was defined according to the ESC HF guidelines available in 2008, and events were classified as new onset with no prior history of HF (de novo-HF) and acute decompensation of chronic HF (worseningHF). Exclusion criteria included age 110 mmHg, whereas levosimendan was rarely used in subjects with higher SBP. Considering the 3 groups described in Table 2, patients taking inotropes with preserved or high SBP were older, had higher body mass index values, hypertensive congestive AHF, higher LVEF,

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and similar comorbidities, including renal failure, anemia, and diabetes. Patients with reduced SBP who were taking inotropes were given nitrates more frequently, whereas i.v. and oral diuretics were used at the same dose in all groups.

Inotropes and outcome Compared to patients who were not treated acutely with inotropes, those treated with inotropes exhibited a longer hospital stay, were admitted more frequently to the intensive care unit (ICU), and had significantly worse short- and long-term outcomes (Table 3). Impressively, total mortality rate at 1 year was 3× higher in subjects treated with this class of agent (50.6% vs. 17.7%; p 140 mmHg;[27] in the ADHERE registry, only 8% of the patients receiving inotropes had an SBP 180/100 mmHg.[8]. In the present Italian survey, about 50% of the patients receiving inotropes had an SBP >110 mmHg, and only 44% had guideline-documented indications for acute adrenergic support. Interestingly, the patients who were treated with inotropes despite adequate SBP exhibited a similar unfavorable outcome. Inotropic therapy was a strong predictor of all-cause mortality independently from SBP at admission, reinforcing the concept that an incorrect indication may have affected prognosis in this preserved SBP group, which is normally at low risk of adverse events.

The limitations of this registry are related to its characteristics. First, the patients were enrolled in cardiology centers, and the observation and registration of clinical profile and treatments was started after enrollment. In many patients admitted with AHF, the therapy begins in the emergency room, and the timing of treatment may influence the outcome. Moreover, our population does not include patients who died in emergency wards or were admitted to other hospital departments. Second, the percentage of CRT/CRT-D and ICD implantations is very low in our population even considering that 43% of the admitted patients were acute de-novo HF. This data, which has been reported also in other registries, may have affected outcome particularly at one year. It is noteworthy that in the future a larger use of implantable device or at least the use of temporary external wearable defibrillators particularly for patients at higher risk of events such as those treated with inotropes, could modify this events’ figure. Moreover, we did not collect data about inotrope dose or treatment timing. We recognize that this information, if available, could have enabled better stratification of patients receiving this class of agent. Furthermore, a log of out- and in-patients admitted to the wards and clinics of the enrolling hospitals was not available. Therefore, we cannot prove the consecutiveness of patient enrollment. However, all enrolling centers were monitored with periodic visits by trained professionals from the coordinating center of the study.

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In summary, this study shows that i.v. treatment with inotropes is performed in nearly 20% of the patients admitted for AHF. This treatment, independently from the agent used, appears to be strongly associated with poor outcome. Although the complex correlation among mortality, severe hemodynamic profile, and inotropes is a statistical challenge in the interpretation of the cause and the effect, our rigorous approach suggests that this class of drugs influences prognosis despite the initial hemodynamic support. As observed before, inotropes are administered to a large percentage of patients with AHF, although SBP, and presumably cardiac output, is still preserved. The ominous effect of the drug is amplified in these patients, suggesting that this inappropriate treatment affected all group outcomes. ACKNOWLEDGEMENTS The authors state that their study complies with the Declaration of Helsinki, that the locally appointed ethics committee has approved the research protocol and that informed consent has been obtained from the subjects (or their guardians). The Steering Committee of the study had full access to the data and takes complete responsibility for the integrity and the accuracy of the data analysis.

CONFLICT OF INTEREST. A.M., F.O., E.C., A.D.L., P.M., M.S. and R.U. have no conflict of interest to disclose. M.M. has participated in speaker bureaus for Servier, advisory boards for Novartis, Bayer and honoraria from Abbott Vascular, Bayer, Corthera, Novartis and Servier. M.G. and D.L. are employees of Heart Care Foundation which conducted the study with an unresctricted grant of research from Novartis, Abbott and Medtronic. A.P.M. is an employee of Heart Care Foundation which conducted the study with an unresctricted grant from Novartis, Abbott and Medtronic and has been a member of study committees for Novartis, Amgen, Cardiorentis and Bayer. L.T. has received research grants from Boston Scientific and Vifor Pharma, has participated in speaker bureaus and advisory boards for Servier, Cardiorentis and St. Jude Medical.

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Rosamond W, Flegal K, Friday G, et al.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69-171.

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Gheorghiade M, Vaduganathan M, Ambrosy A, et al. Current management and future directions for the treatment of patients hospitalized for heart failure with low blood pressure. Heart Fail Rev 2013;18:107-22.

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McMurray JJ, Adamopoulos S, Anker SD, et al.; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787-847.

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Stevenson LW. Clinical use of inotropic therapy for heart failure: looking backward or forward? Part I: inotropic infusions during hospitalization. Circulation 2003;108:367-72.

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Hunt SA, Abraham WT, Chin MH, et al.; American College of Cardiology Foundation; American Heart Association. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53:e1-e90.

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Lindenfeld J, Albert NM, Boehmer JP, et al; Heart Failure Society of America. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010;16:e1-194.

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Abraham WT, Fonarow GC, Albert NM, et al.; OPTIMIZE-HF Investigators and Coordinators. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure

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(OPTIMIZE-HF). J Am Coll Cardiol 2008;52:347-56. 8

Nieminen MS, Brutsaert D, Dickstein K, et al.; EuroHeart Survey Investigators; Heart Failure Association, European Society of Cardiology. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006;27:2725-36.

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Partovian C, Gleim SR, Mody PS, et al. Hospital patterns of use of positive inotropic agents in patients with heart failure. J Am Coll Cardiol 2012;60:1402-9.

10 Abraham WT, Adams KF, Fonarow GC, et al.; ADHERE Scientific Advisory Committee and Investigators; ADHERE Study Group. In-Hospital Mortality in Patients With Acute Decompensated Heart Failure Requiring Intravenous Vasoactive Medications An Analysis From the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57-64. 11 Elkayam U, Tasissa G, Binanay C, et al. Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure. Am Heart J 2007;153:98-104. 12 Oliva F, Mortara A, Cacciatore G, et al.; IN-HF Outcome Investigators. Acute heart failure patient profiles, management and in-hospital outcome: results of the Italian Registry on Heart Failure Outcome. Eur J Heart Fail 2012;14:1208-17. 13 Tavazzi L, Senni M, Metra M, et al.; IN-HF (Italian Network on Heart Failure) Outcome Investigators. Multicenter prospective observational study on acute and chronic heart failure. The one year follow-up results of IN-HF Outcome Registry. Circ Heart Fail 2013;6:473-81. 14 Sekhon JS. Multivariate and Propensity Score Matching Software with Automated Balance Optimization: The Matching Package for R. Journal of Statistical Software 2011;42:1-52. 15 Ridgeway G, McCaffrey D, Morral A, et al. Twang: Toolkit for Weighting and Analysis of Nonequivalent Groups. R package version 1.2-5. http://CRAN.R-project.org/ (30 August 2013) 16 Lumley T. Analysis of complex survey samples. Journal of Statistical Software 2004;9:1-19. 17 Metra M, Bettari L, Carubelli V, et al. Use of inotropic agents in patients with advanced heart failure. lessons from recent trials and hopes for new agents. Drugs 2011;71:515-25. 18 Tavazzi L, Maggioni AP, Lucci D, et al.; Italian survey on Acute Heart Failure Investigators.

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Nationwide survey on acute heart failure in cardiology ward services in Italy. Eur Heart J 2006;27:1207-15. 19 Thackraya S, Easthaughb J, Freemantleb N, Cleland JG. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure a meta-regression analysis. Eur J Heart Fail 2002;4:515-29. 20 Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005;142:510-24. 21 De Backer D, Biston P, Devriendt J, et al.; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-89. 22 Cleland JG, Freemantle N, Coletta AP, Clark AL. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 2006;8:105-10. 23 Mebazaa A, Nieminen MS, Packer M, et al.; SURVIVE Investigators. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA 2007;297:1883-91. 24 Mebazaa A, Parissis J, Porcher R, et al. Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med 2011;37:290-301. 25 Hasenfuss G, Teerlink JR. Cardiac inotropes: current agents and future directions. Eur Heart J 2011;32:1838-45. 26 Beanlands RS, Nahmias C, Gordon E, et al. The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: A doubleblind, placebo-controlled, positron-emission tomography study. Circulation 2000;102:2070-5. 27 Gheorghiade M, Abraham WT, Albert NM, et al.; OPTIMIZE-HF Investigators and Coordinators. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 2006;296:2217-26.

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APPENDIX Steering Committee L. Tavazzi (Chairman), G. Cacciatore, A. Chinaglia, A. Di Lenarda, A.P. Maggioni, A. Mortara, M. Metra, F. Oliva, M. Senni Coordinating Center ANMCO Research Center (A.P. Maggioni, M. Gorini, I. Cangioli, L. Gonzini, D. Lucci, 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, U.S.C. 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, Medicina (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 Sofia-Cervello 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, 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); Vibo Valentia (L. Anastasio)

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LEGENDS

Figure 1. Odds Ratio ± 95% confidence limits for in-hospital and 1-year all cause mortality in patients taking inotropes as compared to those who did not, according with different cut-off values of systolic blood pressure (SBP) at entry. It is noteworthy that even for the lowest values of SBP the risk remained at least twice higher or more in patients treated with inotropes than in those who did not both at short and mid-term follow-up. Table 1. Baseline clinical characteristics according to the use of inotropic agents No Inotropes

Inotropes

Dopamine

Dobutam.

Levosim.

(n=1495)

(n=360)

(n=258)

(n=143)

(n=73)

73±11

70±12*

71±13

71±12

68±14

Age ≥70 (yrs), %

66.2

56.9†

59.3

60.8

49.3

Females, %

40.8

35.6

36

32.2

42.5

Ischemic etiology, %

40.0

51.9†

50.0

53.1

46.6

Hypertensive etiology, %

22.7

5.8†

6.6

3.5

2.7

De-Novo HF, %

44.4

37.2†

40.7

30.1

48

BMI ≥30 (kg/m2), %

29.5

24.8

21.3

28.3

26.1

BMI

Treatment with inotropes and related prognosis in acute heart failure: contemporary data from the Italian Network on Heart Failure (IN-HF) Outcome registry.

In the recent Italian Network on Heart Failure (IN-HF) Outcome registry, including 1,855 patients with acute heart failure (AHF), we reviewed the use ...
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