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Acute Decompensated Heart Failure : What is New ?

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Acute Decompensated Heart Failure : What is New ?

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Acute Decompensated Heart Failure : What is New ?

  1. 1. Prof. U. C. SAMAL MD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVS Ex-HOD Medicine & Prof. Cardiology Patna Medical College, Patna, Bihar Past President, Indian College of Cardiology Permanent & Chief Trustee, ICC-HFFI National Executive Member, Cardiological Society of India President, CSI Bihar Acute Decompensated Heart Failure : What Is New ?
  2. 2. The best physician for a patient with HF would be one with excellent training, extensive experience, and superb judgment with regards to all aspects of the disease He or she would not necessarily follow guidelines slavishly Management for Heart Failure : Summary J N Cohn Cir Heart Fail 1 87-88
  3. 3. • diuretics • ultrafiltration Vasodilators • nitroglycerin • nesiritide • nitroprusside INOTROPES • dobutamine • dopamine • levosimendan • nitroprusside Fluid retention or redistribution ? “dry out” “warm up & “dry out” Assessment of hemodynamic profile : therapeutic implications Adapted from Stevenson L W, Eur Heart j
  4. 4. HF Management: Principal changes from the 2008 guidelines o An expansion of the indication for mineralocorticoid receptor antagonists (MRAs) o A new indication for the sinus node inhibitor Ivabradine o An expanded indication for cardiac resynchronisation therapy (CRT) o New information on the role of coronary revascularisation in HF (PCI / CABG) o Recognition of the growing use of ventricular assist devices (LVAD) o The emergence of transcatheter valve interventions ESC guidelines for the diagnosis and treatment of acute and chronic heart failure
  5. 5. Linking Short- term intervention with long-term benefit: What is needed? Better understanding of Acute Heart Failure pathophysiology ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 Reviewed by Ponikowski
  6. 6. Initial, short-term therapies [hours-days] Target Traditional therapeutic approach Effects on long-term outcome Alleviate Congestion i.v. Diuretics ? May be detrimental Reduce ↑ LV filling pressure i.v. nitrates ? Potentially favourable Hypoperfusion poor cardiac performance i.v. inotropes Detrimental Dissociation between symptomatic improvement, clinical stabilisation & favourable long-term outcome Modified From Pang P S et al Eur Heart J 2010 31.784 -93
  7. 7. Primary outcome : Mortality Standard Oxygen Therapy Versus Non Invasive Ventilation Non-invasive ventilation [eg CPAP] should be considered in dyspnoeic patients with pulmonary oedema and a respiratory rate > 20 breaths / min to improve breathlessness and reduce hypercapnia and acidosis. Non-invasive ventilation can reduce blood pressure and should not generally be used in pts with a SBP <85mmHg [ and BP should be monitored regularly when this treatment is used ] [class IIa, level B] 3 CPO Study ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012
  8. 8. Multiple reflections of ultrasound beams ultrasound beams ultrasound beams Comet-tails echographic image Normal echographic image horizontal lines Regular intervalReverberations Transducer Transducer Edematous Interlobular Septa Normal Interlobular Septa Ultrasound Comet-Tail Images: A Marker Of Pulmonary Edema A: Typical comet-tail artifacts: hyperechogenic, coherent vertical bundles with narrow basis spreading from the transducer to the further border of the screen. This artifact is composed of multiple microreflections of the ultrasound beam. A B B: Normal subject, with regular, parallel, roughly horizontal hyperechogenic lines due to the lung-wall interface. Chest. 2005;127(5):1690-1695.
  9. 9. The four chest areas per side considered for complete eight zone lung ultrasound examination. These areas are used to evaluate for the presence of interstitial syndrome. Areas 1 and 2 denote the upper anterior and lower anterior chest areas, respectively. Areas 3 and 4 denote the upper lateral and basal lateral chest areas respectively.
  10. 10. HF: Monitoring to predict/ prevent ADHF admissions • Devices: Externally applied Impedance Cardiography (PREDICT study 211 pts) • Internally placed devices measuring intra thoracic impedance(PARTNER 2HF: CRT device with Impedance monitoring): predicted subsequent admission for ADHF • PA / LA/ LVEDP monitoring devices Usefulness uncertain for mortality benefit
  11. 11. Heart Failure Risk Scores Circ HF 2013 End point: Death/ transplant/ Assist device • Heart Failure Survival Score(200pts): – IHD, QRS>120ms, LVEF, Resting HR, mean BP, O2 consumption, ser Na • Seattle Heart Failure model: (1100pts) – Age, LVEF, NYHA class, SBP, Diuretic dose, Na+, uric acid, ser. Chol., lymph. count - Sex, IHD, QRS >120ms, ICD, CRT, betablockers, ACEI, Statins, Allopurinol,
  12. 12. Heart Failure Risk Scores • SHOCKED predictor: (900pts): Age>75, NYHA>II, AF, COPD, CKD, LVEF<20%, DM • PACE: (900 pts) PVD, Age >70, Creatinine >2, EF < 20%, • ADHERE registry( for acute mortality): SBP, Ser creatinine and BUN • Frankenstein: BNP , 6′WT
  13. 13. In multivariable models, nearly all tested covariates performed similarly across LVEF strata for the outcome of death from any cause, as well as for HF-related and all-cause hospitalizations. Conclusions—We found that in a large, diverse contemporary HF population, risk assessment was strikingly similar across all LVEF categories. These data suggest that, although many HF therapies are uniquely applied to patients with reduced LVEF, individual prognostic factor performance does not seem to be significantly related to level of left ventricular systolic function. (Circ Heart Fail. 2013;6:635-646.)
  14. 14. Post Discharge Multi disciplinary Management Program • Cardiac Rehabilitation: periodic follow up, education, optimize drug treatment, general medical care, exercise program, ensure access to hospital care • Palliative Care: frequent hospitalization, not listed fro transplant or mechanical circulatory support, poor quality of life, dependence for daily needs, close to end of life • Heart failure team: practitioner, nurse, pharmacist, dietician, psychologist, physiotherapist
  15. 15. Conclusion • Acute Heart Failure, is a medical emergency and rapid, coordinated multi disciplinary approach can significantly reduce mortality. • Stabilized patients of AHF, to have GDMT/ devices/ revascularization as indicated • At discharge: patient education, counseling, compliance with GDMT and frequent clinic visits can prevent re- hospitalization for AHF
  16. 16. Proposed classification for patients who present with acute heart failure syndromes ACCF/AHA stage Explanation of stage Worsening chronic HF (75%) Stage C C: structural heart disease with prior or current symptoms of HF Advanced HF (5%) Stage D D: refractory HF requiring specialized interventions De novo HF (20%) Stage B most common, but also Stage A Also neither A nor B B: structural heart disease but without signs or symptoms of HF A: at high risk for HF but without structural heart disease or symptoms of HF
  17. 17. Phases of acute heart failure syndromes management PHASES PHASES GOALS AVAILABLE TOOLS Initial or emergency department phase of management Treat life threatening conditions Establish the diagnosis Determine the clinical profile Identify and treat precipitant Disposition Examples: STEMI - reperfusion therapy History, physical exam, EKG, X-ray, natriuretic peptide level BP, HR, signs (e.g. pulmonary oedema), ECG, X-ray, laboratory analysis, echocardiography History, physical exam, X-ray, ECG, laboratory analysis No universally accepted risk-stratification method Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793
  18. 18. Phases of acute heart failure syndromes management PHASES PHASES GOALS AVAILABLE TOOLS IN – HOSPITAL PHASE Monitoring and reassessment Assess right and left ventricular pressures Assess and treat (in the right patient) other cardiac and non-cardiac conditions Assess for myocardial viability Signs/symptoms, HR, SBP, ECG, orthostatic changes, body weight, laboratory analysis (BUN/Cr, electrolytes), potentially BNP SBP (orthostatic changes, valsalva manoeuvre), echocardiography, BNP/NT- proBNP, PA catheter Echo-Doppler, cardiac catheterization, electrophysiology testing MRI, stress testing, echocardiography, radionuclear studies Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793
  19. 19. Phases of acute heart failure syndromes management PHASES PHASES GOALS AVAILABLE TOOLS DISCHARGE PHASE Assess functional capacity Re-evaluate exacerbating factors (e.g. non- adherance, infection, anaemia, arrhythmias, hypertension) and treat accordingly Optimize pharmacological therapy Establish post-discharge planning 6 min walk test Examples: physical therapy, education for diet control and medication, evaluation for sleep apnoea ACCF/AHA and ESC guidelines Discharge instructions including body weight monitoring, smoking cessation, medication adherance, follow-up Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793
  20. 20. Drug failures in acute heart failure Trial name Drug tested Patients enrolled VMAC Nesiritide Decompensated CHF Excluded SBP < 90 mmHg, Mean SBP > 124 mmHg No LVEF cut point OPTIME Milrinone Decompensated systolic heart failure, not requiring inotropes Excluded SBP < 80 mmHg, Mean SBP = 120 mmHg Mean LVEF = 23% VERITAS Tezosentan Acute heart failure Two out of four-↑BNP, pulmonary oedema, CXR congestion, LVEF < 40%, Mean LVEF = 20% in VERITAS I and 28% in VERITAS II Mean SBP = 131 in VERITAS I and 132 in VERITAS II SURVIVE Levosimendan Acute decompensated HF requiring inotropes LVEF < 30%, Mean LVEF = 24$ Mean SBP-116 mmHg
  21. 21. Trial name Drug tested Patients enrolled REVIVE -2 Levosimendan Acute decompensated HF Symptomatic despite i.v. diuretic LVEF < 35%, Excluded SBP > 90 mmHg EVEREST Tolvaptan Hospitalized for decompensated CHF LVEF ≤ 40%, Excluded SBP < 120 mmHg Mean LVEF = 27.5%, Mean SBP= 120 mmHg PROTECT I and II Rolofylline Acute heart failure, Impaired renal function ↑BNP ASCEND-HF Nesiritide Acute decompensated heart failure Drug failures in acute heart failure
  22. 22. Some new therapeutic agents for acute heart failure and their potential targets Agent For patients with these clinical features Diuretics, vasopressin antagonists, adenosine antagonists Patients with signs of fluid overload, high BNP Vasodilators Normal to high SBP, high BNP Inotropes Low SBP, signs of Hypoperfusion Renal preservation agents Renal dysfunction Myocardial protection agents CAD, or ongoing ischaemia
  23. 23. Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793 ESC divides pts. Into six clinical profiles 1.Worsening or decompensated chronic HF 2.Pulmonary Oedema 3.Hypertensive HF 4.Cardiogenic shock 5.Isolated right HF 6.ACS and HF with the explicit acknowledgement that there is overlap between groups The ACCF/AHA divides patients based on presenting clinical profile into three main groups: (i) volume overload, manifested by pulmonary and/or systemic congestion, usually due to increases in blood pressure (BP), (ii) severely reduced cardiac output often with hypotension, and (iii) combined volume overload and cardiogenic shock ESC Guidelines
  24. 24. Initial Therapeutic Management Target Therapeutic example Mechanism of action Side effects Alleviate congestion IV furosemide Water and sodium excretion Electrolyte abnormalities Reduce elevated LV filling pressures IV nitrates Direct relaxation of vascular smooth muscle cells through various mechanisms Hypotension, decreased coronary perfusion pressure Poor cardiac performance Inotropes Activate camp or calcium sensitization resulting in improved contractility; also powerful vasodilators: in effect, inodilators Hypotension, arrhythmias, myocardial damage, association with increased morbid events Tachycardia and increased systemic blood pressure (i.e. in cases of excessive sympathetic tone Beta-blockers: IV esmolol may be used when HF is related to AF with RVR and/or severe hypertension Blockade of beta-1 and beta-2 receptors Bradycardia,hypotension, negative inotropy; however given short half- life of esmolol, these side effects should be short lived Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793
  25. 25. Short- and long-term novel therapies for AHF syndromes Short term Long term Both Levosimendan [LIDO, CASINO, SURVIVE] ? ? Nesiritide[ROSE, DOSE-AHF] Relaxin [RELAX-AHF] Myosin Activators Omecamtiv Mecarbil [ATOMIC-AHF] RyR2 stabilizers/ rycals Cinaciguat (UIT) Adenosine regulating agents Stresscopin Istaroxime [HORIZON-HF] Ularitide [TRUE-AHF, SIRIUS II, URGENT] Urocrotins [UNICORN] Hypertonic Saline Ultrafiltration [RAPID-CHF, UNLOAD] IABP EECP [PEECH] CAFA IMT Direct renin Inhibitors (DRI) [ASTRONAUT] Macronutrients Micronutrients CRT/AICD Adenosine Antagonists [PROTECT, REACH UP rolofylline] Vasopressin Antagonists [EVEREST, TACTICS-HF] Digoxin [DIG] CD-NP Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793 modified 2013
  26. 26. Clinical RELEVANCE of promising novel biomarkers(AHFS) Biomarker Diagnosis Prognosis Therapy guidance Cardiac Production NT-proBNP and BNP ++++ ++++ ++ Solely Serum Sodium ++ ++ ++ No Serum Creatinine ++ ++ ++ No MR-proANP +++ ++++ Likely similar to NT- ProBNP/BNP Solely sST2 + ++++ ? Not Exclusively Hs troponin-I [EFFECT] + ++++ ? Solely MR-proADM - ++++ ? No Cystatin C - ++++ ? No NGAL - ++++ ? No GDF-15 - +++ ? Not Exclusively β- Trace protein - +++ ? No Gal-3 - +++ ? Not exclusively CRP - ++ ? No TNF-α - ++ ? No IL-6 - ++ ? No PTX3 - ++ ? Unknown MPO - ++ ? Not exclusively ET-1 - ++ ? Not exclusively Copeptin - ++ ? No PCT ++ ++ ++ No 27 Clinical Chemistry 58:1 127–138 (2012)
  27. 27. Summary of the main utility biomarkers in AHFS Biomarkers Diagnosis & pathophysiology Adverse prognosis Serum sodium n.v. 136-145mmol/L AHF –RAA activation <120mmol/L Serum creatinine n.v. 0.5 – 1.5mg/dL Cardiorenal syndrome > 150µmol/L Serum uric acid n.V m 3.1 -8.1mg/100ml, 2.2 -7.1mg/100ml AHF –oxidative stress >1.5mg/dl >9.8mg/dl NPs [blood & serum] BNP NT-pro-BNP MR-pro-ANP v.n. HF cut off <100pg/ml; >400pg/ml <400pg/ml; >2000pg/ml <120pmol/l; 120pmol/l AHF left ventricular volume and pressure overload [heart muscle stretching] > 1000pg/ml > 5000pg/ml -- ST2 [serum] n.V 1.75 -34.3U/ml AHF overload >10ng/ml
  28. 28. Summary of the main utility biomarkers in AHFS Biomarkers Diagnosis & pathophysiology Adverse prognosis PCT [serum] Cut off 0.05ng/ml 0.05 -0.5ng/ml local infection 0.5-2ng/ml systemic infection 2-10ng/ml SIRS – sepsis >10ng/ml sepsis NGAL [serum and urine] Cut off 150ng/ml serum, 130ng/ml urine Cardiorenal syndrome >100ng/ml Copeptin [serum] Median 3.7pmol/l AHF vascular alterations >54.2pmol/l MR-proADM [SERUM] AHF vascular alterations >2.15nmol/l ADMA AHF oxidative stress
  29. 29. Modes of presentation of ADHF Clinical status Heart rate SBP mmHg Cl L / min /m3 Pulmonary capillary wedge pressure mmHg Conges tion killip/for rester Diuresis Hypope rfusion End organ hypoperfusion I acute decompensated congestive heart failure + / - Low normal / high Low normal / high Mild elevation K II / F II + +/- _ II Acute heart failure with hypertension/ hypertensive crisis Usually elevated High +/- >18 K II-IV/ F II / III +/- +/- + WITH CNS symptoms III Acute heart failure with pulmonary edema + Low normal Low Elevated K III / F II + +/- - IVa Cardiogenic shocka/low-output syndrome + Low normal Low, <2.2 >16 K III-IV/ F I-III Low + + IVb Severe cardiogenic shock >90 <90 <1.8 >18 K IV / F IV Very low ++ + V High-output failure + +/- + +/- K II / F I-II + - - VI Right-sided acute heart failure Usually low Low Low Low F I +/- +/-, acute onset +/-
  30. 30. Patient presenting with dyspnea Differential diagnosis cardiac -- Consider acute coronary syndrome Physical exam, chest x-ray, ECG, BNP level Treatment option for HF with SBP <90mmHg or shock –diuretics, inotropes, vasodilators and /or nesiritide to follow BNP <100pg/ml BNP 100-500pg/ml BNP >500pg/ml HF very unlikely [2%] Clinical suspicion of HF or past h/o HF HF very likely [95%] HF highly probable [90%] Differential diagnosis noncardiac -- consider COPD, pulmonary embolism, asthma, pneumonia, sepsis Treatment option for HF with SBP > 90mmHg -- diuretics with nesritide esp. with CKD & pulmonary congestion may consider adding vasodilators if hypertensive may consdider adding inotropes for poor perfusion Treatment option -- •Diuretics as required •Consider nesritide if any of the following - Scr>1.5mg/dl, CrCl <60ml/min, BUN >10mg/dl, pulmonary congestion or for border line hemodynamic instability
  31. 31. Comprehensive Assessment Potential targets Method of assessment Congestion JVP, Body wt, peripheral edema LV function, valvular ds, wall motion abnormalities, aneurysm ECHO Doppler, MRI, Nuclear imaging Ischaemia Pharmacological or exercise testing with imaging CAD Cardiac catheterization and angiography Ventricular dyssnchrony [wide QRS] Electrocardiogram Viable but dysfunctional myocardium Low dose dobutamine ECHO, MRI
  32. 32. Myocardium Coronary arteries Electrical system Valves •Surgery •Procedural •Statins •Per EDC guidelines Pericardium LV dysfunction •ACE-I or ARB •Beta blockers •Aldosterone antagonist •Hydral / ISDN •Digoxin •Macronutrients •Micronutrients •Metabolic modulators CAD •Anti platelet •Statins •Revascularization •Other ESC guideline recommended therapy for secondary prevention Sudden cardiac death •ICD •B- blockers •Aldesterione antagonist Ventriculasr dysschrony •CRT +/- ICD Atrial fibrillation •Rate control – digoxin – b- blocker, non dihydropyridine ca channel blockers •Warfarin •Rhythm control •MAZE procedure Congestion – [ salt restriction, diuretics, ultrafiltarion, vasopressin antagonists] Hypertension [ACE I or ARB, diuretics, other per ESC guidelines Enhance adherence [education, disease management, performance improvement system Cardiac reconstruction [five overacting thematic targets – myocardium, coronary arteries, electrical system, pericardium, valves]
  33. 33. 0 10 20 30 40 50 right HF hypertensive HF cardiogenic shock pulmonary edema decompensated HF De novo AH ADCHF all Mortality % Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793
  34. 34. AHFS : NOT VERIFIED Similarities and differences between acute MI & AHFS in hospitalization in the US Incidence 1 million per year 1 million per year Mortality Pre hospitalization In hospital After discharge [ 60-90 d] High 3-4% 2% ? 3-4% 10% Myocardial injury Yes Likely Pathophysiological target Clearly defined [coronary thrombosis] Uncertain Clinical benefits of interventions in published clinical trial Beneficial Minimal / no benefit or deleterious compared with placebo ACC / AHA recommendation LEVEL A NONE
  35. 35. Acute Heart Failure Syndrome(s) • Acute heart failure (AHF) is defined as a rapid onset or change in the signs and symptoms of HF, resulting in the need for urgent therapy. • Symptoms are primarily the result of severe pulmonarycongestion due to elevated left ventricular (LV) filling pressures(with or without low cardiac output). • AHFS can occur in patientswith preserved or reduced ejection fraction (EF). • Concurrentcardiovascular conditions such as coronary heart disease (CHD),hypertension, valvular heart disease, atrial arrhythmias, and/or noncardiac conditions (including renal dysfunction, diabetes,anemia) are often present and may precipitate or contributeto the pathophysiology of this syndrome
  36. 36. EBM in AHFS? • The first randomizedplacebo-controlled AHFS trials were published as late as 2002. Cuffe MS, et al. for the Outcomes of a Prospective Trial of Intravenous Milrinone forExacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Effects of short-term, intravenous milrinone on acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002; 287: 1541–1547. PublicationCommittee forthe VMAC Investigators. Intravenous nesiritide vs nitroglycerin fortreatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002; 287: 1531–1540 • None of the placebo-controlled AHFS studies conducted to datehas shown either a consistent improvement of in- hospital orpostdischarge survival or a
  37. 37. AHFS – Goals of treatment • † Emergency treatment phase • Improve symptoms • Restore oxygenation • Improve organ perfusion and haemodynamics • Limit cardiac/renal damage • Minimize ICU length of stay • † In-hospital management phase • Stabilize patient and optimize treatment strategy • Initiate appropriate (life-saving) pharmacological therapy • Consider device therapy in appropriate patients • Minimize hospital length of stay • † Discharge planning phase • Plan follow-up strategy • Educate and initiate appropriate lifestyle adjustments • Provide adequate secondary prophylaxis • Prevent early readmission • Improve quality of life and survival
  38. 38. AHFS: which appropriate targets of therapy ? • Traditionally, reduction in pulmonary capillary wedge pressure (PCWP)and/or increase in cardiac output. • However, other therapeutictargets may include blood pressure control, myocardial protection,neurohormonal modulation, and preservation of renal function.
  39. 39. Treatment of AHFS Patients • The emergencytreatment phase
  40. 40. Patient Selection and Treatment Congestion at Rest YesNo Warm & Dry PCWP normal CI normal (compensated) Cold & Wet PCWP elevated CI decreased Cold & Dry PCWP low/normal CI decreased Vasodilators Nitroprusside Nitroglycerin Inotropic Drugs Dobutamine Milrinone Calcium Sensitizers Normal SVR High SVR Low Perfusion at Rest No Yes Warm & Wet PCWP elevated CI normal Natriuretic Peptide Nesiritide or Stevenson LW. Eur J Heart Fail. 1999;1:251.
  41. 41. Adverse Drug Effects • Non-Potassium-Sparing Diuretics Intravenous loop diuretics may improve symptoms and fluid loss initially but also may contribute to renal function decline.This may be related not only to intravascular volume depletionbut also to further neurohormonal activation resulting in avasomotor nephropathy. • Intravenous loop diuretics may be associated with worse outcomes in AHFS patients. • Inotropic Therapy Intravenous inotropes increase myocardial oxygen consumption, causing myocardial damage in the setting of hibernating myocardium. Use of inotropes has consistently been associated with increasedmortality. • Vasodilators Excessive vasodilatation in AHFS may lead to blood pressure decrease, potentially exacerbating myocardial ischemia and renal hypoperfusion.
  42. 42. AHFS: which appropriate targets of therapy ? Perspectives • Managing fluids, • Preserving renal function
  43. 43. Vaso active drugs in ADHF Relaxin: Serelaxin • RELAX AHF:1160 pt. of ADHF with preserved SBP >115 mmHg. • Serelaxin 30 ug/kg/day x48 hrs or Placebo • Significant improvement in dyspnoea scale • No impact on short term mortality/ HF readmission at 60 days, though 180 day mortality was significantly lower. • Hypotensive episodes higher but renal dysfunction less than placebo group • No limitation: dobutamine milrinone (increase intercellular calcium in myocytes leading to tachycardia and arrhythmias, levosimendon calcium sensitiser causes atrial and ventricular arrhythmias, and like milrinone may be limited by hypotension. • FDA grants Breakthrough Therapy designation to Novartis' serelaxin (RLX030) for acute heart failure.
  44. 44. Biology of Relaxin and Potential Beneficial Effects in Heart Failure Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M - Curr Heart Fail Rep (2010) Endogenous peptide associated with pregnancy, and acts through relaxin receptor: reduce inflammation, decrease fibrosis, attenuate ventricular remodeling, increase vasodilation, promote renal blood flow, increase vascular endothelial growth factor, and angiogenesis. ↓Inflammation↓Inflammation ↓Fibrosis↓Fibrosis ↑Vasodilation↑Vasodilation Renal effectsRenal effects AngiogenesisAngiogenesis Relaxin ReceptorRelaxin Receptor RelaxinRelaxin Pregnancy associated endogenous peptide Relaxin ReceptorRelaxin
  45. 45. Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator Malik Fl, et al. Science 2011; 331:1439-43 Teerlink JR, et al. Lancet 2011; 378:667-75; Cleland JGF, et al. Lancet 2011; 378:676-83 Mechanochemical Cycle of Myosin • • Increases duration of systole • Increases stroke volume • No Increase in myocyte calcium • No change in dp/dtmax • No increase in MVO2 ATOMIC-AHF Phase 2; 613 pts .X 48 hrs random IV dose 115; 230; 310 ng/ml. ATOMIC-AHF Phase 2; 613 pts .X 48 hrs random IV dose 115; 230; 310 ng/ml. COSMIC-HF chronic oral therapy; oral alone or IV to oral transition. COSMIC-HF chronic oral therapy; oral alone or IV to oral transition. Omecamtiv mecarbil increases the entry rate of myosin into the tightly- bound, force-producing state with actin “More hands pulling on the rope”
  46. 46. • Efficacy – OM did not meet the 1° endpoint of dyspnoea relief – Appeared to improve dyspnoea in Cohort 3 – Trends towards reduction of worsening HF • Safety – Overall SAE profile and tolerability similar to placebo – Increase in troponin; no clear relationship to OM concentration – Numerical imbalance in MIs in Cohort 3 – No evidence of pro-arrhythmia • Pharmacology – PK similar to healthy volunteers and stable HF patients – Systolic ejection time significantly increased consistent with MOA – Small fall in heart rate & rise in systolic BP at higher doses Summary Though at present investigational the drug of the future in AHF Janccin B: New Heart failure inotrope could be ‘Holy Grail’. IMNG Medical Media September 5, 2013 John J. V. McMurray et al, on behalf of the ATOMIC-AHF Investigators and Patients
  47. 47. Levosimendan enhances contractility by increasing responsiveness of myofilaments to calcium. The cardiac myosin activator Omecamtiv mecarbil stimulates myosin adenosine triphosphatase (ATPase), thereby increasing force generation. Istaroxime inhibits activity of plasma membrane sodium-potassium ATPase and increases the activity of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Mechanism of action of novel contractility-enhancing medications. Omecamtiv mecarbil (Modified from Tavares M, Rezlan E, Vostroknoutova I, et al. New pharmacologic therapies for acute heart failure. Crit Care Med 2008; 36[Suppl]:S112-S120.)
  48. 48. • Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation of sarcoplasmic reticulum calcium ATPase. • 120 AHF pts and reduced systolic function. Three sequential cohorts of 40 patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h infusion. The first cohort received 0.5 g/kg/min, the second 1.0 g/kg/min, and the third 1.5 g/kg/min istaroxime or placebo. • In patients hospitalized with HF, istaroxime improved PCWP and possibly diastolic function. In contrast to available inotropes, istaroxime increased SBP and decreased HR. Istaroxime Mihai Gheorghiade et al JACC 2008:03;015
  49. 49. Vaso active drugs in ADHF Ularitide • Synthetic form of Urodilantin: human natriuretic peptide produced in kidney: induces natriuresis and diuresis. Also potent vasodilator( increases intracellular cyclic GMP) and increased renal blood flow) : Two double blind studies have shown favorable outcome in ADHF by symptom improvement and hemodynamics. • Phase 3 trial(TRUE-AHF >2110 pts) - ongoing study.
  50. 50. Investigational drugs in ADHF Adenosine A1 receptor antagonist: Rolofylline • Preserve GFR, improve diuresis, increase sodium excretion by kidney • Phase 2 trial: better relief of dyspnoea and lesser renal dysfunction • Phase 3 trial: PROTEC:2033 pts.: negative trial with none of the primary end points significant and safety was questioned due to neurological side effects: seizure and stroke
  51. 51. • Small studies have indicated that adenosine A1 receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. • 2,033 AHF pts, volume overload, eCrCl 20 - 80 ml/min, and elevated BNP randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. • In this large, phase III clinical trial, the adenosine A1 receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. Rolofylline
  52. 52. •Effects of rolofylline on endpoints in relation to baseline renal function. •The secondary morbidity/mortality endpoint, the risk of death or cardiovascular or renal rehospitalization through day 60, was lower in the rolofylline group compared with the placebo group only in patients with a baseline eCrCl 30 ml/min (hazard ratio: 0.64; 95% CI: 0.43 to 0.95), but not in the other subgroups Rolofylline
  53. 53. • Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. • In a prospective, double-blind, randomized trial, we assigned 308 patients with ADHF to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or a high dose (2.5 times the previous oral dose). • Among patients with ADHF, there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. Furosemide
  54. 54. • The study tests the hypothesis that in patients admitted with acutely decompensated heart failure (ADHF), achievement of adequate body hydration status with intensive medical therapy, modulated by combined bioelectrical vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP) measurement, may contribute to optimize the timing of patient’s discharge and to improve clinical outcomes. • 300 ADHF pts underwent serial BIVA and BNP measurement. Therapy was titrated to reach a BNP value of 250 pg/ml, whenever possible. • Our study confirms the hypothesis that combined BNP/BIVA sequential measurementshelp to achieve adequate fluid balance status in patients with ADHF and can be used to drive a ‘‘tailored therapy,’’ allowing clinicians to identify high-risk patients and possibly to reduce the incidence of complications secondary to fluid management strategies.
  55. 55. Ultrafiltration
  56. 56. AHFS: which appropriate targets of therapy ? • Contractility • Diastole
  57. 57. •Urocortins are a recently discovered group of peptide hormones of the corticotropin releasing factor family. They bind with a strong affinity to the CRH-R2 receptor, which is highly expressed in the myocardium and in the vascular endothelium. •Urocortins exhibit potent inotropic and lusitropic effects on rat and sheep hearts and activates a group of myocyte protective pathways collectively known as ‘reperfusion injury salvage kinase’. •In healthy humans show that brief intravenous infusions of urocortin 2 in healthy humans induce pronounced dose-related increases in cardiac output, heart rate, and left ventricular ejection fraction while decreasing systemic vascular resistance; similar effects were seen in HF patients. Urocortins
  58. 58. AHFS: which appropriate targets of therapy ? • Vasomotion
  59. 59. • Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. • We randomly assigned 7141 patients • Coprimary end points were the change in dyspnea at 6 and 24 hours, and the composite end point of rehospitalization for heart failure or death within 30 days. • Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. • It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. Nesiritide
  60. 60. These molecules have been engineered to combine the beneficial aspects of different natriuretic peptides into a single molecule while minimizing potentially negative actions. CD-NP is a combination of C-type natriuretic peptide (CNP) and Dendroapsis NP (DNP). Although lacking natriuretic effects, CNP is a more selective venodilator than BNP, thus reducing the risk of significant hypotension. On the other side, DNP possesses significant natriuretic activity, at the expense of possible hypotensive effects. The chimeric peptide CD-NP combines the favourable natriuretic effects of DNP with the venodilatory profile of CNP, reducing the risk for harmful side effects. Preliminary studies in AHFS patients are ongoing. Chimeric natriuretic peptides
  61. 61. • Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC, second messenger that internalizes the message carried by intercellular messengers such as peptide hormones and NO) activator that is being developed as a first-in-class treatment for acute decompensated heart failure (ADHF). It acts independently of the sGC ligand nitric oxide. • Cardioprotective effects in animal models, and pilot clinical studies found that it was well tolerated, unloaded the heart and increased cardiac output. • This placebo-controlled, randomized, double-blind, multicenter, international phase IIb study investigated the safety and efficacy of intravenous cinaciguat (per-protocol) as add-on to standard therapy in 139 patients with ADHF (NYHA functional class III and IV; pulmonary capillary wedge pressure [PCWP] ≥ 18 mmHg). • Cinaciguat rapidly and significantly reduced PCWP and PVR and increased cardiac output in patients with ADHF, without impairing cardiac or renal function. Hypotension occurred in some patients; further dose titration studies are therefore required to establish the optimal dosing strategy for this promising new therapy. Cinaciguat JACC Mar 9,2010 Vol:55 issue 10A
  62. 62. Adenosine regulating agents •This new class of drugs, whose prototype is represented by acadesine, has been developed to mimic the protective effects of adenosine during ischaemia. •Acadesine exerts its pharmacological actions by increasing adenosine bioavailability and by activating 50adenosine monophosphate (AMP) signalling cascade via its metabolite 5-aminoimidazole-4-carboxamide riboside (ZMP). •The first mechanism leads to multiple anti-ischaemic effects (maintenance of endothelial function and vasodilation, inhibition of platelet aggregation and neutrophil activation), whereas the latter ameliorates glucose uptake and free fatty acid oxidation thus increasing ATP synthesis. Importantly, acadesine exerts its actions only in areas undergoing net ATP catabolism (such as ischaemic tissues) thereby avoiding potentially harmful peripheral vasodilator effects. Acadesine
  63. 63. Stresscopin Human stresscopin is a corticotropin-releasing factor type 2 receptor selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and LVEF. 62 pts with HF and LVEF ≤ 35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of stresscopin or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in SVR were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of stresscopin without significant changes in HR or SBP. No statistically significant reductions in PCWP were seen with any dose tested in the primary analysis, although a trend towards reduction was seen. In HF patients with reduced LVEF and CI, ascending doses of stresscopin were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP.
  64. 64. In-Hospital Management Phase • This phase begins once the patient is stabilized and dyspneais improved. • Because a significant number of patients continueto have signs and symptoms of HF, the goals of this phase arecontinued hemodynamic and symptomatic improvement while preventing myocardial and renal injury. • Patients who are not treated withACE inhibitors, angiotensin receptor blockers, ß-blockers,or aldosterone antagonists should receive these therapies, asrecommended by recent guidelines
  65. 65. AHFS: in-hospital management (ADHERE/OPTIMIZE-CHF/EURO-HF)
  66. 66. Discharge-Planning Phase • Despite the clinical evidence supporting the use of implantablecardiac defibrillators and cardiac resynchronization therapyin patients with chronic HF and systolic dysfunction, theirrole in AHFS patients is not clear. • The available data suggest that a significant number of AHFSpatients are not being evaluated for potential beneficial surgicalprocedures that include myocardial revascularization, LV reconstruction, mitral valve surgery, or cardiac transplantation.
  67. 67. AHFS where are we? Where are we going? • AHFS is a complex condition with substantial morbidity and mortalityand enormous utilization of health resources and cost. • Thereare numerous challenges in caring for this population. • UniformAHFS classification is currently lacking, and management strategiesvary markedly. • There is a general consensus that to reduce mortality,morbidity, and the economic burden of AHFS, systematic researchefforts on clinical application and translation of promisingbasic science results are needed. • Pathophysiologically basedinterventions (eg, cardiorenal syndrome) may be particularlyappealing. • A special focus should be on choice of appropriatemanagement strategies, including minimizing the use of drugswith adverse effects and development and validation of knownprognostic markers to guide AHFS interventions.
  68. 68. …of note, every large published clinical trial conducted in patients with AHFs has been negative in terms of efficacy, safety, or both. …However, most international multicenter clinical trials completed to date were conducted on fairly undifferentiated populations of patients with AHFs. ….homogeneous pathophysiological disease states within the heterogeneity of aHFs is of paramount importance to clinical trial design and aHFs therapy. … Future trials conducted in aHFs must abandon the ‘one-sizefits- all’ approach in favor of an approach that takes into account the varied and distinct pathophysiologies of aHFs.
  69. 69. Milton Packer 2008 JCF • … Yet, despite substantial advances in our understanding and management of heart failure, we have had • few successes and many failures. • Nearly 1,000 new drugs and devices have been developed for the treatment of heart failure duringthe past 20 years, but only 9 have received regulatory approval and are being used in the clinical setting. • Most of our efforts to correct fluid retention, stimulate the inotropic state of the heart, and modulate neurohormonal systems have not predictably improved the condition of patients with HF…
  70. 70. Apelin
  71. 71. rhBNP D R I M K R G S S S S G L G F C C S S G SGQVM K V L R R H KPS Effects of Nesiritide Venous, arterial, coronary VASODILATION CARDIAC INDEX Preload Afterload PCWP Dyspnea HEMODYNAMIC CARDIAC No increase in HR Not proarrhythmic Aldosterone Endothelin Norepinephrine SYMPATHETIC AND NEUROHORMONAL SYSTEMS Fluid volume Preload Diuretic usage NATRIURESIS DIURESIS RENAL
  72. 72. Risk Scores to Predict Outcomes in HF Risk Score Reference (from full-text guideline)/Link Chronic HF All patients with chronic HF Seattle Heart Failure Model (204) / http://SeattleHeartFailureModel.org Heart Failure Survival Score (200) / http://handheld.softpedia.com/get/Health/Calculator/HFSS-Calc- 37354.shtml CHARM Risk Score (207) CORONA Risk Score (208) Specific to chronic HFpEF I-PRESERVE Score (202) Acutely Decompensated HF ADHERE Classification and Regression Tree (CART) Model (201) American Heart Association Get With the Guidelines Score (206) / http://www.heart.org/HEARTORG/HealthcareProfessional/GetWithTheGuide linesHFStroke/GetWithTheGuidelinesHeartFailureHomePage/Get-With-The- Guidelines-Heart-Failure-Home- %20Page_UCM_306087_SubHomePage.jsp EFFECT Risk Score (203) / http://www.ccort.ca/Research/CHFRiskModel.aspx ESCAPE Risk Model and Discharge Score (215) OPTIMIZE HF Risk-Prediction Nomogram (216)
  73. 73. Diuretics in Hospitalized Patients Patients with HF admitted with evidence of significant fluid overload should be promptly treated with intravenous loop diuretics to reduce morbidity. If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose and should be given as either intermittent boluses or continuous infusion. Urine output and signs and symptoms of congestion should be serially assessed, and the diuretic dose should be adjusted accordingly to relieve symptoms, reduce volume excess, and avoid hypotension. I IIaIIb III I IIaIIb III
  74. 74. Diuretics in Hospitalized Patients (cont.) The effect of HF treatment should be monitored with careful measurement of fluid intake and output, vital signs, body weight that is determined at the same time each day, and clinical signs and symptoms of systemic perfusion and congestion. Daily serum electrolytes, urea nitrogen, and creatinine concentrations should be measured during the use of intravenous diuretics or active titration of HF medications. When diuresis is inadequate to relieve symptoms, it is reasonable to intensify the diuretic regimen using either: a. higher doses of intravenous loop diuretics. b. addition of a second (e.g., thiazide) diuretic. I IIaIIb III I IIaIIb III
  75. 75. Diuretics in Hospitalized Patients (cont.) Low-dose dopamine infusion may be considered in addition to loop diuretic therapy to improve diuresis and better preserve renal function and renal blood flow. I IIaIIb III
  76. 76. Renal Replacement Therapy The Hospitalized Patient
  77. 77. Renal Replacement Therapy Ultrafiltration may be considered for patients with obvious volume overload to alleviate congestive symptoms and fluid weight. Ultrafiltration may be considered for patients with refractory congestion not responding to medical therapy. I IIaIIb III I IIaIIb III
  78. 78. Parenteral Therapy in Hospitalized HF If symptomatic hypotension is absent, intravenous nitroglycerin, nitroprusside or nesiritide may be considered an adjuvant to diuretic therapy for relief of dyspnea in patients admitted with acutely decompensated HF. I IIaIIb III
  79. 79. Arginine Vasopressin Antagonists In patients hospitalized with volume overload, including HF, who have persistent severe hyponatremia and are at risk for or having active cognitive symptoms despite water restriction and maximization of GDMT, vasopressin antagonists may be considered in the short term to improve serum sodium concentration in hypervolemic, hyponatremic states with either a V2 receptor selective or a nonselective vasopressin antagonist. I IIaIIb III
  80. 80. Arginine Vasopressin Antagonists • Risk of liver injury has been described in those with pre-existing liver disease when exposed to AVP antagonists • http://www.fda.gov/Safety/MedWatch/SafetyInformati - accessed 06/04/13
  81. 81. Surgical/Percutaneous/Transcatheter Interventional Treatment of HF Coronary artery revascularization via CABG or percutaneous intervention is indicated for patients (HFpEF and HFrEF) on GDMT with angina and suitable coronary anatomy, especially for a left main stenosis (>50%) or left main equivalent disease. CABG to improve survival is reasonable in patients with mild to moderate LV systolic dysfunction (EF 35% to 50%) and significant (≥70% diameter stenosis) multivessel CAD or proximal LAD coronary artery stenosis when viable myocardium is present in the region of intended revascularization. I IIaIIb III I IIaIIb III
  82. 82. Surgical/Percutaneous/Transcatheter Interventional Treatment of HF (cont.) CABG or medical therapy is reasonable to improve morbidity and cardiovascular mortality for patients with severe LV dysfunction (EF <35%), HF, and significant CAD. Surgical aortic valve replacement is reasonable for patients with critical aortic stenosis and a predicted surgical mortality of no greater than 10%. Transcatheter aortic valve replacement after careful candidate consideration is reasonable for patients with critical aortic stenosis who are deemed inoperable. I IIaIIb III I IIaIIb III I IIaIIb III
  83. 83. Surgical/Percutaneous/Transcatheter Interventional Treatment of HF (cont.) CABG may be considered with the intent of improving survival in patients with ischemic heart disease with severe LV systolic dysfunction (EF <35%), and operable coronary anatomy whether or not viable myocardium is present. Transcatheter mitral valve repair or mitral valve surgery for functional mitral insufficiency is of uncertain benefit and should only be considered after careful candidate selection and with a background of GDMT. Surgical reverse remodeling or LV aneurysmectomy may be considered in carefully selected patients with HFrEF for specific indications including intractable HF and ventricular arrhythmias. I IIaIIb III I IIaIIb III I IIaIIb III
  84. 84. Cystatin C and NT-pro BNP
  85. 85. Furosemide and HTS • Theory: – Offsets the counterproductive neurohormonal up-regulation – transiently improves hemodynamics – promotes renal Na extraction with accompanied net water loss and preservation of renal function • Seems counterintuitive, but in a way, it is “giving the body the very sodium it is trying so hard to retain” Liszowski, Curr Heart Fail Rep. 2010;7:134-39
  86. 86. Furosemide and Hypertonic Saline – ↑ natriuresis and diuresis – Results maintained over time , when continuing PO diuretic therapy and low Na (but not restricted) diet – Better survival at 48 months (55 vs 13%) – Allows more rapid attainment of dry weight – Faster ↓ in BNP (↓ BNP maintained with higher Na diet) – Lower LOS and 30 day readmission rate. – Improvement in renal fn – No adverse cardiac events – US and Brazil w/ ongoing large studies now Paterna, et al. Eur. J Heart Fail 2000;2:305-13 Paterna et al. Clin Drug Interact; 25:165-174 Paterna et al.JACC 2005;45:1887-2003 Licata et al. Am Heart J 2003;145;459-66
  87. 87. (1) Symptom relief. (2) Measures of congestion relief (i.e. improvement in clinical signs). (3) Index hospitalization data (e.g. length of stay). (4) Prevention of end-organ damage (heart and kidney). (5) Post-discharge: death and rehospitalization data. Federal Drug Administration (FDA) Study Group as a general guide for choosing the components of the endpoints to be included when testing different types of drugs in different patient subgroups, although not all of them would be necessary in a single trial Position Statement European Journal of Heart Failure (2011)
  88. 88. Simplified schematic of guanylyl cyclase (GC) pathways, which have cyclic guanosine monophosphate (cGMP) as their second messenger. Nitric oxide is produced by endothelial cells and activates soluble GC in the target cell. ANP and BNP stimulate GC-A (also called NP receptor A), while CNP stimulates GC-B (also called NP receptor B). DNP is a GC-agonist first discovered in snake venom. CD-NP is a chimeric peptide composed of the ring structure and amino terminus of CNP and the carboxyterminus of DNP; it activates both GC-A and GC-B. Natriuretic peptides also bind to the non-GC-linked natriuretic peptide C receptor, the biological significance of which beyond NP clearance is currently unclear. Cyclic GMP modulates cGMP-dependent protein kinase G, cGMP-regulated PDEs, and cGMP-regulated cation channels. The cGMP signal is terminated by PDEs that hydrolyze cGMP to GMP, or by extrusion into the extracellular space. The NPs are degraded by a variety of peptidases. Cyclic GMP signaling can be enhanced by (1) the use of NO mimetics such as nitrovasodilators, (2) direct sGC stimulators, (3) exogenous NPs, (4) inhibiting NP degrading enzymes, and (5) inhibiting the activity of cGMP-hydrolyzing PDEs. ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GC, guanylyl cyclase; DNP, Dendroaspis natriuretic peptide; DPP4, dipeptidyl peptidase IV; NEP, neutral endopeptidase; NO, nitric oxide; PDE, phosphodiesterase; PKG, protein kinase G; RA, natriuretic peptide receptor A; sGC, soluble guanylate cyclase.
  89. 89. Schematic illustrating three different forms of soluble guanylate cyclase and their respective responsiveness to nitrovasodilators, heme-dependent sGC stimulators (e.g., BAY 41-2272), and heme-independent sGC activators (e.g., cinaciguat [also known as BAY 58-2667]). Nitric oxide (NO) and nitrovasodilators only stimulate sGC when it, contains the heme moiety with a ferrous iron (Fe2+ ); furthermore, NO and nitrovasodilators have cGMP- independent actions. BAY 41-2272 also activates only the NO-sensitive sGC but without the cGMP-independent actions of NO and nitrovasodilators. Cinaciguat activates heme-free sGC, which is insensitive to NO, and also inhibits its degradation. The question marks indicate that little is known about the transition between the different forms, their prevalence in health and disease, and their potential restoration to the reduced, NO-sensitive form. cGMP, cyclic guanosine monophosphate; Fe, iron; sGC, soluble guanylate cyclase. (From Boerrigter G, Burnett JC Jr. Soluble guanylate cyclase: not a dull enzyme. Circulation 2009;119(21):2752-2754.)
  90. 90. Mechanism of action of novel contractility-enhancing medications. Levosimendan enhances contractility by increasing responsiveness of myofilaments to calcium. The cardiac myosin activator CK 1827-452 stimulates myosin adenosine triphosphatase (ATPase), thereby increasing force generation. Istaroxime inhibits activity of plasma membrane sodium-potassium ATPase and increases the activity of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). ADP, adenosine diphosphate; ATP, adenosine triphosphate; I-1, protein phosphatase inhibitor-1; P, phosphate; PLB, phospholamban; PP1, protein phosphatase; RyR2, ryanodine receptor; TnC, troponin C; TnI, troponin I; TnT, troponin T. (Modified from Tavares M, Rezlan E, Vostroknoutova I, et al. New pharmacologic therapies for acute heart failure. Crit Care Med 2008; 36[Suppl]:S112- S120.)
  91. 91. Forrester Hemodynamic Subsets Subset Description I: Warm and dry (normal) PCWP 15–18 mmHg and CI >2.2 L/min/m2 II: Warm and wet (congestion) PCWP >18 mmHg and CI >2.2 L/min/m2 III: Cold and dry (hypoperfusion) PCWP 15–18 mmHg and CI <2.2 L/min/m2 IV: Cold and wet (congestion and hypoperfusion) PCWP >18 mmHg and CI <2.2 L/min/m2
  92. 92. Treatment Goals for ADHF •Improve symptoms, especially congestion and low-output sympt. •Restore normal oxygenation •Optimize volume status •Identify etiology •Identify and address precipitating factors •Optimize chronic oral therapy •Minimize side effects •Identify patients who might benefit from revascularization •Identify patients who might benefit from device therapy •Identify risk of thromboembolism and need for anticoagulation •Educate patients concerning medications and self-management of heart failure •Consider and, where possible, initiate a disease-mgt. program
  93. 93. Subset I: Warm and Dry • Therapy is the optimization of oral medications Pharmacotherapy for ADHF Subset II: Warm and Wet • Patient has hypervolemia • IV diuretics and plus or minus vasodilators, nesiritide
  94. 94. Subset III: Cold and Dry • Patient has hypoperfusion • Therapy: oIf PCWP <15 mmHg, IV fluids until PCWP 15–18 mmHg oIf PCWP ≥15 mmHg and MAP <50 mmHg, IV dobutamine oIf PCWP ≥15 mmHg, MAP ≥50 mmHg and compelling indication for inotrope, IV inotrope oIF PCWP ≥15 mmHg, MAP ≥50 mmHg and no compelling indication for inotrope, IV vasodilator Pharmacotherapy for ADHF
  95. 95. Subset IV: Cold and Wet • Patient has hypoperfusion and hypervolemia • Therapy: oIV diuretics oIf MAP <50 mmHg, IV dobutamine oIf MAP ≥50 mmHg and compelling indication for inotrope, IV inotrope oIf MAP ≥50 mmHg and no compelling indication for inotrope, IV vasodilator Pharmacotherapy for ADHF
  96. 96. Discharge Criteria for Patients With ADHF •Treat exacerbating factors (i.e., discontinuation of contraindicated medications) •Patient is at a "dry" weight •Oral medication regimen stable for 24 hours •Patient and family education completed, including clear discharge instructions •Left ventricular ejection fraction documented •Smoking cessation counseling initiated •Follow-up clinic visit scheduled, 7 to 10 days out •Optimal pharmacologic therapy achieved or intolerance documented •Plans for postdischarge management
  97. 97. Ideal properties for an acute heart failure syndromes therapy • Improve signs and symptoms (e.g. dyspnoea) • Improve haemodynamics without adversely effecting heart rate and blood pressure • Improve the neurohumoral profile • Do not cause myocardial and/or kidney damage • Be effective in the context of current evidence-based therapy such as ACE-I and beta-blockers • Demonstrate efficacy in both the acute and chronic setting • Be affordable • Reduce both in-hospital and post-discharge morbidity and mortality.
  98. 98. Differential diagnosis include : • Myocardial infarction • Congestive HF • Pneumonia • COPD exacerbation • Cardiac tamponade • Anxiety • Pulmonary embolism • Asthma
  99. 99. Medicine and dietary non compliance : Cardiac causes •Ischemia •Arrhythmia •Uncontrolled hypertension Noncardiac causes •Infection (pneumonia with or without hypoxia) •Exacerbation of comorbidity (chronic obstructive pulmonary disease) •Pulmonary embolus Toxins (nonsteroidal anti-inflammatory drugs) Volume overload
  100. 100. Istaroxime: Na/K-ATPase Inhibitor Change in left ventricular dP/dtmax comparing istaroxime (PST- 2744) to dobutamine in 5 dogs with chronic ischemic heart failure. No difference was found between PST-2744 and 5 μg/kg/min dobutamine. Both significantly increased dP/dtmax (p < 0.05). Reproduced with permission.J Am Coll Cardiol. 2006;48(12):2397-2409.
  101. 101. Responses of Natriuretic Peptides, ET-1, and Cortisol Mean 95% confidence interval of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cortisol, endothelin-1 (ET-1), and N-terminal pro-brain natriuretic peptide (NT-proBNP) during and after 4-h infusions (shaded in gray) of placebo (open circles) or urocortin (Ucn2) (solid circles). *p < 0.05 and **p < 0.01 indicate significant time-by-treatment interaction in the specific time phase. Chan et al. JACC: Heart Failure Vol. 1,
  102. 102. Responses of Ucn-2, PRA, AngII, Aldosterone, and Ucn-1 Mean 95% confidence interval of plasma aldosterone, angiotensin-II (AngII), plasma renin activity (PRA), urocortin-2 (Ucn2), and urocortin-1 (Ucn1) during and after 4-h infusions (shaded in gray) of placebo (open circles) or Ucn2 (solid circles). yp < 0.001 indicates significant time-by-treatment interaction in the specific time phase. Chan et al. JACC: Heart Failure Vol. 1,
  103. 103. Pulmonary Pressures, Cardiac Output, and Calculated Total Peripheral Resistance Responses Right heart catheter parameters (mean SEM) during and after 4-h infusions (shaded in gray) of placebo (open circles) or urocortin-2 (solid circles). *p < 0.05 and yp < 0.001 indicate significant time-by-treatment interaction in the specific time phase. cTPR ¼ calculated total peripheralChan et al. JACC: Heart Failure Vol. 1,
  104. 104. Congestion at rest Low perfustion at rest No Yes Warm & dry PCWP normal CI normal Warm & wet PCWP elevatedCI normal Cold & dry PCWP low / normal CI decreased Cold & wet PCWP elevated CI decreased Normal SVR High SVR Natriuretic Peptides Nesiritide Or Vasodilators Nitroprusside Nitroglycerine No Yes Inotropic Drugs Dobutamine Milrinone Calcium Sensitizers
  105. 105. Objective: •To evaluate the safety, pharmacokinetics/ pharmacodynamics, and efficacy of IV omecamtiv mecarbil (OM) in patients with acute heart failure (AHF) Hypothesis: •At least 1 dose level of IV OM will be well tolerated and will result in improvement of dyspnoea in subjects with left ventricular systolic dysfunction hospitalised for AHF ATOMIC-AHF Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure Randomised, double-blind, placebo-controlled, sequential cohort study 1:1 randomizations Omecamtiv vs Placebo
  106. 106. Study Design: Sequential Dosing Cohort Cohort 1 Cohort 2 Cohort 3 Omecamtiv Placebo 1:1 Randomization (n≈200) Omecamtiv Placebo 1:1 randomization (n≈200) Placebo Omecamtiv 1:1 randomization (n≈200) DMC DMC Cohort 1 Cohort 2 Cohort 3 15 mg/hr @ 0-4 hr 3 mg/hr @ 4-48 hr Target: 230 ng/mL Cmax: 75-500 ng/mL SET: ~8-55 msec 20 mg/hr @ 0-4 hr 4 mg/hr @ 4-48 hr Target: 310 ng/mL Cmax: 125-700 ng/mL SET: ~14-78 msec 7.5 mg/hr @ 0-4 hr 1.5 mg/hr @ 4-48 hr Target: 115 ng/mL Cmax: 30-250 ng/mL SET: ~3-28 msec Pharmacokinetic simulations Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.

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