1 / 149

Advances in the Management of Heart Failure

Advances in the Management of Heart Failure. Daniel P. Fishbein, M.D . Professor of Medicine Medical Director, Heart Failure and Cardiac Transplantation University of Washington Medical Center. The Scope of the Problem - CHF. 5 million patients with CHF (10 million by 2020)

lynnea
Download Presentation

Advances in the Management of Heart Failure

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Advances in theManagement of Heart Failure Daniel P. Fishbein, M.D. Professor of Medicine Medical Director, Heart Failure and Cardiac Transplantation University of Washington Medical Center

  2. The Scope of the Problem - CHF • 5 million patients with CHF (10 million by 2020) • 500,000 new cases/year • 1,000,000 hospitalizations/year • Incidence doubles with each decade after age 45 • CHF is leading DRG • $29 - 50 billion annual cost; 60% of this cost is spent on hospitalization for ADHF • CHF “epidemic” driven by aging U.S. population, improved survival of ACS, improved long-term survival • 50% of patients have preserved left ventricular ejection fraction

  3. What is Heart Failure? • Heart failure is a syndrome caused by an abnormality of cardiac function that is characterized by impaired exercised tolerance due to shortness of breath and/or fatigue, SOB at rest, systemic and pulmonary venous, and an increase in mortality due to progressive pump failure or ventricular arrhythmias • Final common pathway for a number of cardiac/cardiovascular diseases • Heart Failure with Reduced Ejection Fraction (HFrEF) • Heart Failure with Preserved Ejection Fraction (HFpEF); aka diastolic dysfunction

  4. How do we describe heart failure? • Etiology: ischemic, idiopathic, post-viral, hypertensive, toxic, valvular • NYHA Functional Class - FC I: no symptoms - FC II: symptoms with more than usual activity - FC III: symptoms with minimal activity - FC IV: symptoms at rest • ACC/AHA Stage: course of disease • Clinical assessment: • “wet” or “dry • “cold” or “warm”

  5. Clinical Assessment of Hemodynamics Cold hands Low BP Low pulse pr Tachycardia Confusion Agitation PND, Orthopnea, Edema, JVD, Rales, Effusions

  6. Heart Failure Disease Progression: ACC/AHA Heart Failure Stages Refractory End-Stage HF: Marked symptomsat rest despite maximal medical therapy D Symptomatic HF: Known structuralheart disease, shortness of breath and fatigue, reduced exercise tolerance C Asymptomatic LVD: Previous MI, LV systolic dysfunction, asymptomatic valvular disease B High Risk: Hypertension, coronary artery disease, diabetes, family history of cardiomyopathy A LV=left ventricular, MI=myocardial infarction Adapted from Yancy CW et al. Prim Care Spec Ed 2002;6:15-19.

  7. Causes of Heart Failure with Reduced EF • Coronary artery disease • Ischemic cardiomyopathy • Hypertensive heart disease • Idiopathic cardiomyopathy • Familial cardiomyopathy • Valvular Cardiomyopathy • Aortic stenosis • Aortic insufficiency • Mitral regurgitation • Viral/post-viral/lymphocytic myocarditis • Alcohol-related cardiomyopathy • Thyroid disease (hypo or hyper) • Restrictive/hypertrophic cardiomyopathy • Sarcoid • Cardio-toxic substances: anthracyclines, herceptin, cyclophosphamide, methamphetamines, cocaine • Giant cell myocarditis • Amyloid, hemochromatosis, eosinophilic myocarditis • SLE, systemic sclerosis

  8. Heart Failure Symptoms • Shortness of breath and/or fatigue with activity • Shortness of breath at rest • Shortness of breath with recumbency (orthopnea) or at night (PND) – probably the most specific symptoms for heart failure • Edema • Fatigue • Chest pain • Abdominal swelling, liver pain • Poor appetite • Weight loss • Syncope • Stroke

  9. Heart Failure Signs • Rales • Evidence of pleural effusions • Elevated jugular venous pressure – the most specific physical finding for congestion • S3 – specific for LV dysfunction • Edema - when combined with JVP, specific for HF • MR murmur • Hepatomegaly • Ascites • Cool extremities • Low pulse pressure • Tachycardia

  10. CHF Initial Evaluation • Consider in patients with unexplained SOB especially with JVD, edema, evidence of pulmonary congestion, or unexplained tachycardia. • Obtain an echocardiogram: ventricular dimensions, LV and RV function, assessment of valvular regurgitation and stenosis, assessment of PA and RA pressures. • History, exam, ECG, CXR, Echo, TFTs, chemistries, BUN, creatinine, BNP, CBC with differential, UA, transferrin saturation and ferritin, consider plasma light chains, SPEP and UPEP especially in patients without ventricular dilation • Evaluation for CAD • Coronary angiography • SPECT • Stress PET • Dobutamine stress echo • CT angiography

  11. Diagnostic and Therapeutic Goals in Patients Presenting with Heart Failure • Identify underlying cause(s) of heart failure especially those that may be reversible/treatable : CAD/ischemia, valvular disease, uncontrolled HTN, thyroid abnormalities, alcohol, drugs, iron overload. • Identify conditions that may worsen heart failure: atrial arrhythmia, infection, sleep apnea, urinary obstruction, dietary and medication non-adherence, thyroid abnormalities, alcohol or drug use, meds (NSAIDS, COX 2, TZDs, CCBs, BBs). • Improve symptoms • Prevent/reverse ventricular remodeling • Prevent arrhythmic death (SCD) • Secondary prevention of AMI • Prevent stroke • Improve survival

  12. Heart Failure Pathophysiology Fall in LV Performance  Cardiac output Myocardial Injury Activation of RAAS and SNS ( ET1, AVP, cytokines) Peripheral Vasoconstriction Na/Water Retention Myocardial Toxicity  Gene Expression Remodeling and Progressive Worsening of LV Function Heart Failure Symptoms Morbidity and Mortality

  13. Effect of ACEI in Patients with CHF CONSENSUS and SOLVD CONSENSUS* NYHA Class IV SOLVD Treatment† NYHA Class II-III 80 Placebo (n=126) 60 Placebo (n=1284) Enalapril (n=126) Mortality (%) 40 Enalapril (n=1285) 20 0 0 6 12 18 24 30 36 42 48 Months *Risk reduction 40% (P=0.003). †Risk reduction 16% (P=0.0036). Reprinted with permission from CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435; SOLVD Investigators. N Engl J Med. 1991;325:293-302.

  14. ACEI in Patients with Systolic DysfunctionGarg et al. JAMA 1995;273:1450-6 • > 32 randomized trials of ACEI including enalapril, captopril, ramipril, quinapril and lisinopril • 23% reduction in all-cause mortality largely due to reduction in death from progressive heart failure (HR 0.69) • 35% reduction in mortality or HF hospitalization • Similar effects were observed among different ACEI • Benefit was seen across various subgroups but greatest in patients with the lowest ejection fraction

  15. High vs Low Dose Lisinopril: ATLASPacker et al. Circulation 1999;100: 2312 - 8 • 3164 patients with FC II – IV heart failure and LVEF  30% • Low (2.5-5 mg qd) vs high (32.5 vs 35 mg qd) dose lisinopril • Median follow-up 45.7 months • Hazard Ratios: All-cause mortality 0.92 P = 0.128 CV mortality 0.90 P = 0.073 Mortality and Hosp 0.88 P = 0.002 Mortality and CHF Hosp 0.85 P < 0.001 • ~30% of patients stopped drug and 20% started on open label during course of study

  16. ARBs versus placebo in patients with chronic HF Lee V C et al. Ann Intern Med 2004;141:693-704

  17. ARBs versus ACEI in patients with chronic HF Lee V C et al. Ann Intern Med 2004;141:693-704

  18. ARB and ACEI combinations versus ACE inhibitors in patients with chronic HF Lee V C et al. Ann Intern Med 2004;141:693-704

  19. ACEI and ARB in Chronic Heart Failure • Cornerstone of heart failure therapy • ACEI should be use first – improve survival, decrease hospitalization, inhibit remodeling, improve symptoms, improve functional class, inexpensive, well tolerated • Benefits of ACEI appear to be class-specific • ACEI should be uptitrated every 2-3 weeks to target dose (enalapril 10 mg bid or equivalent) • ARBs should be used in patients intolerant to ACEI (cough, angioedema) (losartan 50 mg bid or equivalent) • The benefits of ARBS are nearly equivalent to ACEI • The benefit of adding and ARB to background ACEI and -blockade has not been clearly established.

  20. Aldosterone Blockade: Rationale • Aldosterone levels associated with mortality in HF • Aldosterone is produced in tissues other than the kidney including heart and blood vessels • Aldosterone production is not completely inhibited by ACEI or ARB • Aldosterone has multiple non-renal effects including SNS activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, vascular injury and decreased arterial compliance, reactive oxygen species, alterations in ion channels, prolonged ventricular repolarization

  21. Spironolactone 25 mg qd in patients with advanced heart failure – The Rales Trial HR= 0.70 HR SCD = 0.71 HR CV H = 0.70 Pitt, B. et al. N Engl J Med 1999;341:709-717

  22. Eplerenone 25 – 50 mg qd in Patients with Recent AMI, EF  40% and CHF or Diabetes – The EPHESUS Trial 22 20 18 16 14 Placebo Eplerenone Cumulative Incidence (%) 12 10 Total Mortality RR = 0.85; P= 0.008 SCD RR = 0.79;P = 0.03 8 6 4 2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Since Randomization

  23. EMPHASIS-HF: Eplerenone in Mild HF and LVEF ≤ 35% Zannad F et al. N Engl J Med 2011;364:11-21.

  24. Aldosterone Blockade in Chronic Heart Failure • Improve survival, decrease SCD, decrease HF hospitalization, improve symptoms and decrease ventricular remodeling in patients with FC III-IV symptoms or HF complicating recent MI • Probably a class effect, fewer side effects with eplerenone • Indicated in patients with NYHA FC 2-4 HF symptoms and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration • Creatinine ≤ 2.5 mg/dL in men and 2.0 mg/dL in women; potassium < 5.0 mEq/L • In EPHESUS and RALES, potassium measured at 48 hours, one, four and five weeks and every three months – study drug decreased or held for K > 5.5 mmol/L

  25. Rates of Hyperkalemiaand DeathAfter Publicationof RALES 500% in spironolactone Rx (p<0.001) 275% in hosp for hyperkalemia (p<0.001) 285% in death due to hyperkalemia (p<0.001) (Juurlink, et al. NEJM 2004;351:543)

  26. Digoxin • Mild positive inotrope • Autonomic effects, sympathoinhibitory,  plasma NE,  plasma renin levels • Improves exercise tolerance and sxs in CHF • DIG Trial - ~7000 pts with mild – moderate CHF randomized to dig or placebo. No difference in mortality but fewer hospitalizations in pts with more severe HF • Increased mortality with higher dig levels • Use as adjunctive therapy in patients with persistent FC III-IV sxs with target dig levels < 0.8 – 1.0 ng/dL

  27. DIG Trial - Mortality N Engl J Med 1997; 336:525-33

  28. DIG Trial –HF Hospitalization N Engl J Med 1997; 336:525-33

  29. The DIG Trial: Survival by Gender HR = 1.23 Rathore, S. S. et al. N Engl J Med 2002;347:1403-1411

  30. The DIG Trial: Event Rates Adjusted for Digoxin Levels (Dose Matters!) Mortality Mortality and Hospitalization Adams et al. JACC 2005; 46: 497 - 504

  31. BETA BLOCKER TRIALS IN CHF DrugPatients Mortality (%) USCHFSG Carvedilol 1,094 65 CIBIS-II Bisoprolol 2,647 32 MERIT-HF Metroprolol XL 3,991 34 Copernicus Carvedilol 2,289 35 BEST Bucindolol 2,708 8.5

  32. CIBIS II HR =0.68 Lancet 1999; 353:9-13

  33. MERIT-HF Placebo Metoprolol CR/XL HR = 0.65 HR SCD = 0.60 Cumulative mortality (%) Follow-up (months) Lancet 1999; 353:2001- 07

  34. COPERNICUS HR = 0.65 HR SCD = 0.67 Packer, M. et al. N Engl J Med 2001;344:1651-1658

  35. Not all -blockers Work BEST Xamoterol Study Group N Engl J Med 2001; 344: 1659-67 Lancet 1990;336:1-6

  36. 150 HF patients on diuretics, ACE inhibitors, +/- digoxin were randomized to double-blind treatment; 122 had EF/hemodynamic assessments at baseline and after 13–15 months of treatment. Achieved doses Metoprolol 124 mg/d vs Carvedilol 49 mg/day Carvedilol vs Metoprolol: LV FunctionMetra M et al. Circulation. 2000;102:546–551. LVEF LV EDV LV ESV 0 16 * -5 14 *** -10 12 -15 10 Absolute Change FromBaseline LVEF units (%) *** mL/m2 -20 8 ** -25 *** 6 -30 4 *** -35 2 *** -40 0 Metoprolol† (n=61) Carvedilol(n=61) *P<.05; **P<.01; ***P<.001. †Metoprololtartrate.

  37. b-Blockers – Time Course of Improvement LVEF % Hall et al JACC 1995; 25:1154-61

  38. -Blocker Dose: MOCHABristow, M. R. et al. Circulation 1996;94:2807-2816 Change in LVEF 6 Month Mortality

  39. Primary endpoint of mortality 40 Metoprolol tartrate (85 mg qd) 30 20 Carvedilol (42 mg qd) Mortality (%) hazard ratio 0.83, 95% CI 0.74-0.93, P = 0.0017 10 0 0 1 2 3 4 5 Time (years) Number at risk Carvedilol 1511 1367 1259 1155 1002 383 Metoprolol 1518 1359 1234 1105 933 352

  40. -Blockers in Heart Failure • Cornerstone of chronic HF therapy •  mortality by 35%,  sudden and heart failure related death • Improve LVEF 8-12% • Benefits may be limited to the BB demonstrated in clinical trials to be effective – these are the BB that should be used to treat heart failure: carvedilol, metoprolol succinate, bisoprolol • Should be used in combination with ACEI or ARB • Initiate at low dose and up-titrate to target doses used clinical trials: carvedilol 25 mg bid; metoprolol succinate 150 mg daily; bisoprolol 10 mg daily

  41. Diuretics • No randomized controlled clinical trials to guide therapy • Goals: improve symptoms by relieving pulmonary and systemic venous congestion without impairing systemic perfusion or renal function and while maintaining normal electrolytes • Most patients need a loop diuretic • Furosemide, bumetanide, torsemide • Need to achieve a threshold dose that results in diuresis • If patients remain volume overloaded, increase the frequency of dosing, especially if using furosemide • In diuretic resistant patients, adding a thiazide or metolazone may be helpful but is associated with more hypokalemia

  42. African-American Heart Failure Trial • African-American patients with NYHA FC III – IV symptoms of heart failure for three months, LVEF  35%, treated with optimal medical therapy • Randomized to placebo vs fixed-dose combination of isosorbide dinitrate and hydralazine 20/37.5 mg tid increasing to 40/75 mg tid • Primary endpoint composite score composed of death, first CHF hospitalization and change in QOL • 1050 patients enrolled – Age 57, Men 59%, FC III 95%, LVEF 24%, ischemic 23%, hypertensive 38%, weight 93 kg, SBP 126 mm Hg, BB 74%, ACE/ARB 86%

  43. A-HeFT HR 0.57 NEJM 2004;351:2049 -57

  44. Hydralazine and Isosorbide • Recommended for African Americans who remain symptomatic despite optimal medical therapy • Reasonable for patients who have persistent symptoms despite optimal medical therapy • Reasonable for patients with severe HF symptoms who are intolerant of ACEI or ARB, especially when this therapy is limited by hypotension or renal insufficiency • No trials data addressing the use of Hyd/ISDN in non-African American patients with persistent symptoms or in patients with ACEI or ARB intolerance • Compliance difficult - tid dosing and side effects

  45. PARAGIGM - HF • Enalapril 10 mg bid vs valsartan 160 mg plus sacubitril 40 mg bid • Sacubitril is an neprilysin inhibitor • Neprilysin is a neutral endopeptidase that degrades several endogenous vasoactive peptides including natriuretic peptides, bradykinin, and adrenomedullin • Inhibition of neprilysin increases levels of these peptides and counters neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling

  46. PARADIGM-HF: Enalapril vs Valsartan and Neprilysin Inhibitor Sacubitril Pitt B et al. N Engl J Med 2014;370:1383-1392.

  47. Sudden Cardiac Death In CHF • ~ 50% of deaths in patients with CHF are due to SCD • SCD is the primary mode of death in patients with less severe CHF • SCD risk factors: CAD, poor LV function, history of syncope, symptomatic ventricular arrhythmias • Primary prevention strategies are limited by the lack of specific predictors of SCD – ambient ectopy, EP testing, signal averaged ECG are not useful screening studies. It has not yet been possible to identify those patients without a prior history of symptomatic arrhythmias who are at highest risk • Conventional antiarrhythmic drugs increase risk of SCD • ACEI, beta-blockers, and aldosterone receptor antagonists decrease SCD risk

  48. MADIT II Survival in Patients with Prior MI and LVEF ≤ 30% HR = 0.69 P = 0.007 Moss AJ. et al. N Engl J Med 2002; 346:877

  49. SCD-HeFT - Mortality HR 97.5% CI P-Value Amiodarone vs Placebo 1.01 0.86, 1.30 0.529 ICD Therapy vs Placebo 0.77 0.62, 0.96 0.007

  50. Sudden Cardiac Death SCD-HeFT Heart Failure Trial Mortality by NYHA Class: ICD vs. Placebo Class II Class III 48% 46% HR 97.5% CI 1.16 0.84, 1.61 32% HR 97.5% CI 0.54 0.40, 0.74 20%

More Related