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Scompenso Cardiaco Acuto: Nuove Acquisizioni

Scompenso Cardiaco Acuto: Nuove Acquisizioni. Abbiamo veramente a disposizione nuovi approcci terapeutici ?. Fabrizio Oliva. Cardiologia 2 Insufficienza Cardiaca e Trapianto. Milano, 20 Settembre 20007. Goals of Treatment of Acute Heart Failure. Improvement of symptoms

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Scompenso Cardiaco Acuto: Nuove Acquisizioni

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  1. Scompenso Cardiaco Acuto: Nuove Acquisizioni Abbiamo veramente a disposizione nuovi approcci terapeutici ? Fabrizio Oliva Cardiologia 2 Insufficienza Cardiaca e Trapianto Milano, 20 Settembre 20007

  2. Goals of Treatment of Acute Heart Failure Improvement of symptoms Clinical stabilization Favorable effects on long-term prognosis + Avoidance / limitation of myocardial damage • Required •  of symptoms with = clinical course • or ~ symptoms with  clinical course Nieminen M, Böhm M, Drexler H, Filippatos GS, Jondeau G, Hasin Y, Lopez-Sendon J, Mebazaa A, Metra M, Rhodes A, Swedberg K. Acute Heart Failure Guidelines. Eur Heart J 2005; 26:384-416

  3. Goals of Treatment of Acute Heart Failure ESC Task Force on Acute Heart Failure • Hemodynamics •  pulmonary wedge pressure to < 18 mm Hg •  cardiac output and/or stroke volume • Symptoms, clinical & laboratory signs •  dyspnea •  edema /  body weight / diuresis /  SAO2 •  creatinine, transaminases… •  BNP • Clinical course •  i.v. infusion duration •  ICU or hospital stay duration •  incidence of rehospitalizations •  mortality

  4. Classificazione strumentale e clinica dello scompenso cardiaco Ipoperfusione tissutale 3,5 3 2,5 2,2 1,5 1 0,5 H-I H-II C-I Diuretici Vasodilatatori: NTG, nitroprussiato C-II Normale Perfusione normale Umido e caldo Secco e caldo Lieve ipoperfusione Edema polmonare H-III H-IV IC I/m/m2 C-III C-IV Somministrazione di fluidi Pressione arteriosa normale: vasodilatatori Pressione arteriosa bassa: Inotropi o vasopressori Ipoperfusione severa Shock ipovolemico Shock cardiogeno Secco e freddo Umido e freddo | | | | | | | | | 0 5 10 15 18 20 25 30 35 40 Congestione polmonare PCWP mmHg Ipovolemia lieve severa Modificata da: A Forrester et al. and LW Stevenson et al.

  5. Vasodilation Is Required to Normalize Ventricular Filling Pressures IV Diuretic Monotherapy Causes Reflex Vasoconstriction, Increased Afterload, and Decreased Cardiac Index 100 IV furosemide + nitroprusside 80 IV furosemide alone 60 Maximal Stroke Volume (%) 40 20 0 0 10 20 30 40 Pulmonary Capillary Wedge Pressure (mm Hg) 25 class IV patients: furosemide alone or with IV nitroprusside. Adapted from Stevenson LW, Tillisch JH. Circulation. 1986;74:1303–1308.

  6. Nesiritide Mechanism of Action • Recombinant human B-type natriuretic peptide (BNP) BNP NPR-A GTP cGMP NO Vasodilation Natriuresis Diuresis Kuhn M. Circ Res. 2003;93:700-709.

  7. Intravenous Nesiritide versus Nitroglycerin for the Treatment of Decompensated Heart Failure Dyspnea Pulmonary Wedge Pressure P=.03 P=.19 100 0 P=.56 80 -2 60 * + * -4 * + 40 Mean change, mm Hg Proportion of patients, % * + * + * + -6 20 Placebo (n=142) Nitroglycerin (n=143) Nesiritide (n=204) -8 0 -20 -10 0 1 2 3 -40 Time, h Placebo Nesiritide Nitroglycerin Minimally/markedly worse Moderately better VMAC Investigators, JAMA 2002; 287:1531 No change Markedly better Minimally better

  8. ADHERE: In-Hospital Mortality and Use of Parenteral Vasoactive Medications Results of Comparative Mortality Analysis of Nesiritide Treatment vs Nitroglycerin, Milrinone or Dobutamine Favors Other Agent Favors Nesiritide Nitrogycerin; n = 5,902(Nesiritide; n = 4,573) P=0.300 Milrinone; n = 1,631(Nesiritide; n = 4,830) P=0.0001 Dobutamine; n = 3,437(Nesiritide; n = 4,431) P=0.0001 1 2 0 ADJUSTED Odds Ratio(and confidence intervals) Journal of Cardiac Failure, October, 2003; 9(5) (Suppl): S81 (Abstract 298); presented at HFSA, 2003

  9. Effects of Nesiritide on Serum Creatinine Nesiritide ≤0.015 mcg/kg/min Versus All Control Therapies P=0.006 Sackner-Bernstein JD, et al. Circulation. 2005;111:1487-1491.

  10. Nesiritide (n = 485) Mortality, % Control (n = 377) Days Effect of Nesiritide on Mortality Meta-Analysis of 3 Nesiritide Trials* Unadjusted: hazard ratio 1.86 (95% CI, 1.02-3.41), P=0.04 Adjusted for study: hazard ratio 1.80 (95% CI 0.98-3.31), P=0.057 *NSGET, VMAC, and PROACTION trials Sackner-Bernstein JD, et al. JAMA. 2005;293:1900

  11. Classificazione strumentale e clinica dello scompenso cardiaco Ipoperfusione tissutale 3,5 3 2,5 2,2 1,5 1 0,5 H-I H-II C-I Diuretici Vasodilatatori: NTG, nitroprussiato C-II Normale Perfusione normale Umido e caldo Secco e caldo Lieve ipoperfusione Edema polmonare H-III H-IV IC I/m/m2 C-III C-IV Somministrazione di fluidi Pressione arteriosa normale: vasodilatatori Pressione arteriosa bassa: Inotropi o vasopressori Ipoperfusione severa Shock ipovolemico Shock cardiogeno Secco e freddo Umido e freddo | | | | | | | | | 0 5 10 15 18 20 25 30 35 40 Congestione polmonare PCWP mmHg Ipovolemia lieve severa Modificata da: A Forrester et al. and LW Stevenson et al.

  12. Levosimendan • Utilizes a dual mechanism of action • Increases calcium myofilament responsiveness through binding to cardiac troponin C • Opens ATP-sensitive potassium channels in vascular smooth muscle cells and in cardiac myocytes Lido Trial Increase in Cardiac Output ≥30% and a Decrease in PCWP ≥25% P= 0.022 Follath et al. Lancet 2002

  13. RandomizationStratified by country and previous heart failure SURVIVE Study Scheme Levosimendan 12 µg/kg bolus 0.1 - 0.2 µg/kg/min, 24 h • Hospitalized for ADHF • LVEF ≤ 30% • Clinical need for inotropic therapy after IV diuretics and/or IV vasodilators: • Oliguria • And/or dyspnea at rest • And/or hemodynamic impairment Dobutamine ≥ 5 µg/kg/min, ≥ 24 h 180 d 24 h 0 1 h • At baseline: • No adjustment of Levosimendan loading dosefor concurrent medications Mebazaa et al. JAMA 2007

  14. :LEVOSIMENDAN: Studio SURVIVE Mebazaa et al. JAMA 2007;297,1883-1891

  15. Admission Medications Cleland JGF et al. Eur Heart J. 2003 Fonarow GC, et al. J Am Coll Cardiol. 2004 Filippatos G and Zannad F Heart failure Rev 2007

  16. If Clinical Situation Does Not Improve With Vasodilators and Diuretics? AHF Vasodilators Diuretics Levosimendan Dobutamine/ Milrinone Dopamine / Nor-Adrenaline if shock with low BP Assist devices Surgery

  17. Effects of Long-term Carvedilol on the Cardiac Index Response to Inotropic Agents Enoximone Dobutamine *** *** 2.0 2.0 *** *** 1.5 1.5 *** *** *** *** *** 1.0 1.0 *** Change from baseline (L/min/m2) Change from baseline (L/min/m2) *** *** *** *** 0.5 0.5 *** ** *** ** * 0.0 0.0 P = 0.0001 P = 0.13 -0.5 -0.5 0 5 10 15 20 0 0.5 1 1.5 2 Dose of dobutamine (ng/kg/min) Dose of enoximone (mg/kg) Control Metra, Dei Cas et al. J Am Coll Cardiol 2002; 40:1248 During long-term carvedilol

  18. Effect of Milrinone on SurvivalKaplan-Meier Survival Curves to 60 Days by Heart Failure Etiology and Treatment Assignment OPTIME-CHF Trial: Sub-Group Survival 100 98 96 94 92 90 88 86 Milrinone Non-ischemic Placebo Non-ischemic Survival, % Placebo Ischemic Milrinone Ischemic 0 10 20 30 40 50 60 Days Felker GM, et al. J Am Coll Cardiol. 2003;41:997-1003.

  19. Without b-Blockers With b-Blockers LIDO Effect of b-Blockers Subset Analysis of Patients Enrolled in the LIDO Study * LEVO, n = 103 DOB, n = 100 * +b +b +b +b † † *P=0.01; †P=0.03 With b-Blockers Follath F, et al. Lancet. 2002;360:196-202.

  20. Hazard Ratios for Patients on -Blockers at Baseline Appeared to Favor Levosimendan Favors Dobutamine Favors Levosimendan Interaction p-value 0.014 Day, Group 5 b-blocker users* b-blocker non-users 14 b-blocker users* b-blocker non-users 31 b-blocker users* b-blocker non-users 90 b-blocker users* b-blocker non-users 180 b-blocker users* b-blocker non-users p-value = 0.01 Hazard Ratio (95% CI) * Within 24 hours of study drug infusion

  21. SURVIVE Favors Dobutamine Favors Levosimendan Interaction p-value 0.053 0.023 0.046 Day, Group 5 Previous history of CHF No previous history of CHF 14 Previous history of CHF No previous history of CHF 31 Previous history of CHF No previous history of CHF 90 Previous history of CHF No previous history of CHF 180 Previous history of CHF No previous history of CHF 0.5 2 88% had history of CHF 12% had no previous history of CHF Hazard Ratio (95% CI) Mebazaa et al. JAMA 2007;297,1883-1891

  22. SURVIVEMean Change from Baseline in BNP Average baseline value: ~1,300 pg/ml (P<0.0001) Mebazaa et al. JAMA 2007;297,1883-1891

  23. LevosimendanEffetti “Short term” • Nei primi 5 giorni: • Riduzione della dispnea • Riduzione BNP • Miglioramento sopravvivenza in pz. in terapia beta-bloccante • Nei primi 30 giorni: • Miglioramento della sopravvivenza in pz. con CHF

  24. :LEVOSIMENDAN: Studio SURVIVE • Possibili prospettive di studio: • Solo pz con peggioramento di insufficienza cardiaca cronica • Evitare il bolo iniziale (riduzione PA nelle prime ore vs. Dobutamina) e personalizzare durata infusione. • Criteri di impiego clinico: • Pz non responsivi a dobutamina • Pz in trattamento con beta-bloccante

  25. Antagonisti della VasopressinaTOLVAPTAN • Antagonista dei recettori della vasopressina • Effetto “aquaretico” (perdita di liquidi non associata a perdita di sodio) • Possibile efficacia nei soggetti iponatriemici • Possibile efficacia nei soggetti non responsivi al diuretico • Dagli studi preliminari a confronto con il placebo: • Efficacia nella decongestione • Interesse a valutare l’impiego in acuto e in cronico

  26. TOLVAPTANStudio EVEREST • Età >18 a., FE <.40 • Insufficienza cardiaca cronica NYHA III/IV • Scompenso congestizio entro 48 h dall’ingresso • End-point: • Mortalità totale • Mortalità cardiovascolare o ospedalizzazione per causa cardiaca • Peso, diuresi, segni e sintomi di scompenso nei primi giorni Tolvaptan 30 mg/die

  27. TOLVAPTANStudio EVEREST Gheorghiade M et Al JAMA 2007

  28. TOLVAPTANStudio EVEREST Gheorghiade M et Al JAMA 2007

  29. Antagonisti della VasopressinaTOLVAPTAN • Efficacia sintomatica nello scompenso congestizio senza eccesso di effetti indesiderati. • Non efficace in cronico nell’insieme dei pazienti. • Interesse a valutare l’efficacia in sottogruppi specifici: • Pz iponatriemici • Pz non responsivi al diuretico

  30. More than 50% of Patients Have Little or no Weight Loss During Hospitalization Fonarow GC. Rev Cardiovasc Med. 2003; 4 (Suppl. 7): 21

  31. Fluid Removal by Ultrafiltration Ultrafiltration removes fluid from the blood at the same rate that the fluid can be naturally recruited from the tissue. This “balanced diuresis” maintains sufficient intravascular volume during the restoration of the body’s fluid balance, decreasing the risk of hypotension. In addition, the electrolyte composition of blood and ultrafiltrate remains in balance, resulting in removal of excess fluid

  32. ULTRAFILTRATION EUPHORIA Trial:Length of Stay RAPID Trial:Total Fluid Removal 48 Hrs P=0.028 ml Bart BA JACC 2005 Costanzo MR JACC 2005

  33. Primary End PointWeight Loss at 48 Hr Primary End PointWeight Loss at 48 Hr ULTRAFILTRATION UNLOAD Trial Primary end point: weight loss at 48 h Costanzo MR JACC 2007

  34. ULTRAFILTRATION UNLOAD Trial Primary End Point: Dyspnea Score at 48 Hr Costanzo MR JACC 2007

  35. ULTRAFILTRATION UNLOAD Trial Freedom From Re-hospitalization for Heart Failure Costanzo MR JACC 2007

  36. ULTRAFILTRATION UNLOAD Trial Safety end points • No clinically significant differences at each assessment interval in serum BUN, Sodium, Chloride and Bicarbonate levels • During treatment, a serum potassium level <3.5 mEq/L occurred in 1 (1%) patient in the ultrafiltration group and in 9 (12 %) patients in the standard care group (p=0.018) • Episodes of hypotension during the first 48 hours after randomization were similar in the ultrafiltration 4 (4.4%) and standard care 3 (3%) Costanzo MR JACC 2007

  37. ULTRAFILTRATION Possible Indications for UF In Patients with HF • Diuretic resistance • Volume overload and worsening renal function on standard medical therapy • Volume overload refractory to vasoactive drugs • Perioperative volume overload

  38. Acute Heart FailureComments • High mortality • The therapy has remained pratically unchanged for 50 y • Guidelines based on little evidence • Adherence to guidelines low • CHF in hospital warrants aggressive management • The three secrets to optimally managed AHFS: • Rapid therapy • Tailored therapy • Reassess frequently • It’s time do dedicate resources and research to this orphan field

  39. www.degasperis.it Questa presentazione sarà disponibile al più presto sul sitodella Fondazione De Gasperis nella sezioneArea Medici

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