Treatment of Heart Failure

1. Treatment of Heart Failure

2. Take-home points HF is a syndrome, not a single disease Structural or functional defects Diminished blood flow or tissue oxygenation Multiple evidence-based treatment options available across dz spectrum Review 2006 HFSA guidelines New treatment options are available Shift from CHF -> HF Less limiting Many pts with HF don�t present with volume overloadShift from CHF -> HF Less limiting Many pts with HF don�t present with volume overload

4. NYHA: I � cardiac dz, but asymptomatic II � dyspnea with heavy exertion III � dyspnea with light exertion IV � dyspnea at rest ACC/AHA A: risk for HF B: asymptomatic HF C: symptomatic HF D: refractory/end stage HFNYHA: I � cardiac dz, but asymptomatic II � dyspnea with heavy exertion III � dyspnea with light exertion IV � dyspnea at rest ACC/AHA A: risk for HF B: asymptomatic HF C: symptomatic HF D: refractory/end stage HF

6. Correlates with new definitions of hypertension Think of ACC/AHA class A as �pre-CHF� Allows earlier identification of at-risk populationCorrelates with new definitions of hypertension Think of ACC/AHA class A as �pre-CHF� Allows earlier identification of at-risk population

7. Pathophysiology of HF Cardiac injury �> depressed cardiac function ?poor tissue perfusion Cardiac output must increase Activation of neurohormonal axis Norepi, AVP, angiotensin II, endothelin Chronic NH release is dysfunctional Alterations in HR, contractility Myocardial hypertrophy and ischemia Norepi � increases cardiac contractility and rate, systemic vasoconstriction and sodium retention AVP (arginine-vasopressin) � causes water retention to expand plasma volume Angiotensin II � promotes systemic vasoconstriction, induces sodium retention, promotes pathologic remodeling of the myocardium Endothelin � potent vasoconstrictor, with positive inotropic effects; stimulates further secretion of AVP and aldosteroneNorepi � increases cardiac contractility and rate, systemic vasoconstriction and sodium retention AVP (arginine-vasopressin) � causes water retention to expand plasma volume Angiotensin II � promotes systemic vasoconstriction, induces sodium retention, promotes pathologic remodeling of the myocardium Endothelin � potent vasoconstrictor, with positive inotropic effects; stimulates further secretion of AVP and aldosterone

8. Causes of heart failure Ischemic disease/MI Cardiomyopathy Hypertension Genetic disorders Valvular abnormalities Infection Alcohol Arrhythmias Hyperthyroidism Anemia

9. Classification of HF Which side of heart is affected Left (more common) Right (right-sided MI, pulmonary HTN) Which heart function is affected Systolic (? contraction and EF, dilated LV) Diastolic (? relaxation,) Failure of LV filling Contractile function and EF usually normal

10. Progressive algorithm Each stage involves all modalities of previous stage, plus some additional tx options Right now, I want you to focus on treatments in stage A � remember, this is pre-CHF; it involves primarily preventive measures, the most important of which is HTN controlProgressive algorithm Each stage involves all modalities of previous stage, plus some additional tx options Right now, I want you to focus on treatments in stage A � remember, this is pre-CHF; it involves primarily preventive measures, the most important of which is HTN control

12. 32 y/o AA male presents with progressive DOE over the past 3 weeks - unable to walk one flight of stairs without resting. He also complains of severe weight gain over this time period (>15 lbs), feeling bloated, and unable to sleep because he feels like he stops breathing. No PMH/meds PE: HR 110s, BP 115/75 JVD to jaw, pitting edema The case of Mr. Jones

13. Signs and sxs of HF DOE, fatigue Orthopnea JVD, enlarged liver Nocturnal cough or DOE S3 gallop Bilateral crackles at lung bases Lower extremity edema

14. What to do with Mr. Jones? What studies do you want to order? What medication first? ACE-I vs. beta blocker Which ACE-I? Which beta blocker? Can I start a beta blocker with bad CHF? When to start diuretics?

15. HF work-up ECG, CXR, echocardiogram CBC, Chem, LFTs, TSH, lipids Baseline BNP Selected patients: Iron panel, HIV, ANA Coronary angiography Endomyocardial biopsy ECG � screen for rhythm disturbance, structural abnormalities, previous MI CXR � pulmonary congestion Echo � systolic vs. diastolic HF, structural abnormalities TSH � hyper- and hypothyroidism can lead to HF CBC � anemias cause high-output HF Renal fx � HF reduces GFR Liver fx � HF causes hepatic congestion Lytes � volume overload and diuretic use causes lyte disturbances Iron panel � hemachromatosis Coronary angio � patients with CP on exertion Biopsy � patients with HF and dilated cardiomyopathy not due to ischemic diseaseECG � screen for rhythm disturbance, structural abnormalities, previous MI CXR � pulmonary congestion Echo � systolic vs. diastolic HF, structural abnormalities TSH � hyper- and hypothyroidism can lead to HF CBC � anemias cause high-output HF Renal fx � HF reduces GFR Liver fx � HF causes hepatic congestion Lytes � volume overload and diuretic use causes lyte disturbances Iron panel � hemachromatosis Coronary angio � patients with CP on exertion Biopsy � patients with HF and dilated cardiomyopathy not due to ischemic disease

16. ACE-inhibitors First-line treatment Beneficial across all functional classes of HF Reduce risk of developing HF in at-risk patients (ALVD, previous MI, > 55 y.o. with vascular disease or DM) Start low, titrate to target (doses shown effective in clinical trials)

19. How much ACE-I?

20. Beta blockers Historically contraindicated, but strong evidence now refutes that Standard therapy in HF Class effect � most studies with carvedilol and metoprolol Start when euvolemic and stable Start low and titrate to max tolerated Historically contraindicated � worsened condition during acute exacerbations (that�s why we now start when pt is relatively stable, not in ICU w/ exacerbation)Historically contraindicated � worsened condition during acute exacerbations (that�s why we now start when pt is relatively stable, not in ICU w/ exacerbation)

21. Have you ever noticed the cool names in cardiology trials? Wow your cardiology colleagues by stating, �well, obviously the COPERNICUS trial proved the effectiveness of carvedilol in patients with severe HF� but I thought it was interesting that the CAPRICORN study was able to extrapolate that effect to those patients who only had post-MI LVD.�Have you ever noticed the cool names in cardiology trials? Wow your cardiology colleagues by stating, �well, obviously the COPERNICUS trial proved the effectiveness of carvedilol in patients with severe HF� but I thought it was interesting that the CAPRICORN study was able to extrapolate that effect to those patients who only had post-MI LVD.�

25. Implications of CARMEN First trial comparing BB monotherapy to ACEI monotherapy Beta blockers by themselves good enough Good alternative in ACE-I intolerant patients Combination therapy is likely best Consensus supports ACE-I first, if tolerant

27. Back to Mr. Jones� Echocardiogram EF 10-20%, global hypokinesis Idiopathic dilated cardiomyopathy Carvedilol 3.125mg bid Lisinopril 5mg daily Lasix 40mg IV BID due to his LE edema Mr. Jones now has a dry cough and is uncomfortable Now what?

29. Candesartan in ACE-I intolerant patients Another study, Val-HeFT looked at valsartan in HF and found: The primary outcomes of the Val-HeFT study was all-cause mortality, and combined all-cause mortality plus morbidity, which included hospitalization for heart failure, cardiac arrest with resuscitation, or need for intravenous support for worsening heart failure.30 After 2 years of follow up, analysis of the data showed no effect of valsartan on all-cause mortality. However, there was a statistically significant risk reduction of 0.87 (95% confidence interval 0.79, 0.96) in the combined outcome of all-cause morbidity and mortality, or a 13% decline (P = 0.009). Candesartan in ACE-I intolerant patients Another study, Val-HeFT looked at valsartan in HF and found: The primary outcomes of the Val-HeFT study was all-cause mortality, and combined all-cause mortality plus morbidity, which included hospitalization for heart failure, cardiac arrest with resuscitation, or need for intravenous support for worsening heart failure.30 After 2 years of follow up, analysis of the data showed no effect of valsartan on all-cause mortality. However, there was a statistically significant risk reduction of 0.87 (95% confidence interval 0.79, 0.96) in the combined outcome of all-cause morbidity and mortality, or a 13% decline (P = 0.009).

30. ACE/ARB combination What if Mr. Jones tolerated the ACE Inhibitor, would it be helpful or harmful add an ARB to his medications? BP 100/80 HR 72 Cr 1.1 K+ 4.1

31. Candesartan added to background therapy (ACE-I and BB) � resulted in statistically significant reduction in CV mortality and HF hospitalizationCandesartan added to background therapy (ACE-I and BB) � resulted in statistically significant reduction in CV mortality and HF hospitalization

32. Poor Mr. Jones� Titrated up meds Carvedilol 6.25 mg bid Lisinopril 20 mg daily Lasix 80 mg bid Still NYHA class III, tired of your continued failure to make him better Now what?

36. So, Mr. Jones is now taking: Coreg 6.25mg bid Lisinopril 20mg daily Spironolactone 25mg qd Lasix 80mg bid His BP and HR still stable but had to D/C spironolactone due to severe increase K+ He is still NYHA Class III Any other medications we can add? Hail to thee, polypharmacy�

37. African American Heart Failure trial: Isosorbide dinitrate and hydralazine added to standard therapy in black malesAfrican American Heart Failure trial: Isosorbide dinitrate and hydralazine added to standard therapy in black males

39. Improvements in all-cause mortality and 1st HF hospitalization Interesting� decreased perceived QOL score compared to placebo� result of additional medication side effects?Improvements in all-cause mortality and 1st HF hospitalization Interesting� decreased perceived QOL score compared to placebo� result of additional medication side effects?

40. How did Mr. Jones do? Mr. Jones was discharged last week in NYHA class II heart failure, but comes back to the ED after gaining 10 lbs with an increase in fatigue and SOB � he�s having trouble walking up one flight of stairs again. BP 95/52 HR 58 Cr 1.5 K+ 3.9 What happened? Which meds should we hold? Should we change anything else?

41. � turns out that Mr. Jones really likes to eat soup. Unfortunately, no one ever told him to read nutrition labels, and he�s been ingesting vast quantities of sodium� turns out that Mr. Jones really likes to eat soup. Unfortunately, no one ever told him to read nutrition labels, and he�s been ingesting vast quantities of sodium

42. Diet and nutrition in HF Sodium restriction (2-3g/day) in all patients with clinical HF Fluid intake < 2 liters in patients with fluid retention and hyponatremia Consider daily MVI supplementation Caloric assessment / supplementation in patients with advanced HF/cachexia

43. A few words about diuretics Mainstay of symptomatic treatment No clinical trials on mortality effects Thiazide diuretics OK in mild HF Most HF patients will eventually require loop diuretics Trick: balancing hypervolemia reduction vs. renal function, electrolytes, hemodynamic stability

45. Diuretic resistance Progression of heart failure Excessive sodium consumption NSAIDS Tactics to overcome Increased dose, more frequent dosing Combine loop and thiazide diuretics Concurrent ACE-I or aldosterone antag. Watch renal function carefully!

47. Digoxin Limited role in HF Does not improve mortality in mild to moderate HF Can reduce hospitalization in poorly controlled patients Narrow therapeutic window (0.125-0.250 mg daily) Watch for digoxin toxicity

50. Mr. Jones redux You started IV lasix 80mg TID and Mr. Jones is not responding � urine output < 1L a day Symptoms worsen to NYHA Class IV JVD to earlobes, bilateral rales Vital signs 95/50 HR 103 Cr still 1.5 K+ stable Any suggestions?

51. Recombinant Human B-type Natriuretic Peptide � Pharmacologic Effects NATRECOR� (nesiritide) has the same 32 amino acid sequence as the endogenous peptide1 Human BNP increases intracellular cGMP, which serves as second messenger to dilate veins and arteries1 Systemic Hemodynamic Effects1,2,3 preload and afterload reduction increased cardiac index no significant increase in heart rate Human B-type Natriuretic Peptide NATRECOR� (nesiritide) is the recombinant form of endogenously produced hBNP, a cardiac hormone secreted largely by the cardiac ventricles in response to pressure and volume overload.1�8 The structure of nesiritide is identical to that of naturally occurring BNP.1,2,6,8 BNP binds NPR-A and increases cGMP production intracellularly.3,4 Nesiritide is cleared from the circulation via 3 routes: receptor-mediated endocytosis, proteolytic degradation by NEP, and renal filtration of intact peptide.3,7�9 Dialysis patients usually do not have significantly elevated BNP levels if they do not have LV dysfunction or LVH.10 Physiologic Effects of NATRECOR� (nesiritide) The hemodynamic effects of NATRECOR� are characterized by balanced venous and arterial dilation, resulting in decreased preload and afterload as assessed by reductions in pulmonary capillary wedge pressure (PCWP), right arterial pressure (RAP), pulmonary pressures, and systemic vascular resistance (SVR). Cardiac index (CI) also increases secondary to afterload reduction in a dose dependent manner. Unlike vasodilators, however, vasodilatory effects of nesiritide are accompanied by no significant increase in heart rate. 1Hobbs RE et al. Am J Cardiol. 1996;78:896 2Mills RM, Hobbs RE. Congest Heart Fail. 2002;9:270 3Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67 4Levin ER et al. N Engl J Med. 1998;339:321 5Fonarow GC. Heart Fail Rev. 2003;8:321 6Hobbs RE et al. Exp Opin Invest Drugs. 2001;10:935 7de Lemos JA et al. Lancet. 2003;362:316 8NATRECOR� (nesiritide) for injection prescribing information. Physicians� Desk Reference�. 58th ed. Montvale, NJ: Thomson PDR; 2004:3100 9Almirez R, Protter AA. J Pharmacol Exp Ther. 1999;289:976 10Cataliotti A et al. Mayo Clin Proc. 2001;76:1111 Colucci WS et al. N Engl J Med. 2000;343:246 Abraham WT et al. J Card Fail. 1998;4:37 Jensen KT et al. Clinic Sci. 1999;96:5 Human B-type Natriuretic Peptide NATRECOR� (nesiritide) is the recombinant form of endogenously produced hBNP, a cardiac hormone secreted largely by the cardiac ventricles in response to pressure and volume overload.1�8 The structure of nesiritide is identical to that of naturally occurring BNP.1,2,6,8 BNP binds NPR-A and increases cGMP production intracellularly.3,4 Nesiritide is cleared from the circulation via 3 routes: receptor-mediated endocytosis, proteolytic degradation by NEP, and renal filtration of intact peptide.3,7�9 Dialysis patients usually do not have significantly elevated BNP levels if they do not have LV dysfunction or LVH.10 Physiologic Effects of NATRECOR� (nesiritide) The hemodynamic effects of NATRECOR� are characterized by balanced venous and arterial dilation, resulting in decreased preload and afterload as assessed by reductions in pulmonary capillary wedge pressure (PCWP), right arterial pressure (RAP), pulmonary pressures, and systemic vascular resistance (SVR). Cardiac index (CI) also increases secondary to afterload reduction in a dose dependent manner. Unlike vasodilators, however, vasodilatory effects of nesiritide are accompanied by no significant increase in heart rate. 1Hobbs RE et al. Am J Cardiol. 1996;78:896 2Mills RM, Hobbs RE. Congest Heart Fail. 2002;9:270 3Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67 4Levin ER et al. N Engl J Med. 1998;339:321 5Fonarow GC. Heart Fail Rev. 2003;8:321 6Hobbs RE et al. Exp Opin Invest Drugs. 2001;10:935 7de Lemos JA et al. Lancet. 2003;362:316 8NATRECOR� (nesiritide) for injection prescribing information. Physicians� Desk Reference�. 58th ed. Montvale, NJ: Thomson PDR; 2004:3100 9Almirez R, Protter AA. J Pharmacol Exp Ther. 1999;289:976 10Cataliotti A et al. Mayo Clin Proc. 2001;76:1111 Colucci WS et al. N Engl J Med. 2000;343:246 Abraham WT et al. J Card Fail. 1998;4:37 Jensen KT et al. Clinic Sci. 1999;96:5

52. Nesiritide Efficacy:Dyspnea Improvement in VMAC Trial Significant improvement� in patient-reported dyspnea at 3 hours VMAC Trial Conclusions: Efficacy The VMAC trial demonstrated that, compared with placebo, nesiritide resulted in significantly improved hemodynamics in patients with ADHF; resulted in rapid and sustained decreases in cardiac filling pressures; and consistently reduced mean PCWP. Nesiritide also significantly reduced dyspnea at 3 hours compared with placebo and the standard of care, nitroglycerin. Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531VMAC Trial Conclusions: Efficacy The VMAC trial demonstrated that, compared with placebo, nesiritide resulted in significantly improved hemodynamics in patients with ADHF; resulted in rapid and sustained decreases in cardiac filling pressures; and consistently reduced mean PCWP. Nesiritide also significantly reduced dyspnea at 3 hours compared with placebo and the standard of care, nitroglycerin. Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531

53. Effect of Nesiritide on Serum Creatinine: VMAC Effect of Nesiritide on Serum Creatinine: VMAC In the VMAC trial, mean changes in serum creatinine obtained at the various time points were similar for nesiritide and IV nitroglycerin (both added to standard of care) for all patients. Nesiritide (n = 273) Nitroglycerin (n = 219) Baseline creatinine (mg/dL) Mean ? SD 1.6 ? 1.06 1.6 ? 0.99 Range 0.4�11.1 0.5 � 9.5 Change from baseline (mg/dL) Day 2 0 ? 0.41 0 ? 0.31 Day 5 +0.1 ? 0.59 0 ? 0.42 Day 14 +0.2 ? 0.85 +0.2 ? 0.6 Day 30 +0.1 ? 0.75 +0.1 ? 0.73 Subanalysis of patients with renal insufficiency (serum creatinine ?2.0 mg/dL), including those requiring chronic dialysis was conducted. Mean serum creatinine for nesiritide and IV nitroglycerin were also similar. Nesiritide (n = 60) Nitroglycerin (n = 44) Baseline creatinine (mg/dL) 3.0 ? 1.5 3.0 ? 1.4 Day 2 creatinine 2.9 ? 1.6 2.8 ? 1.4 Day 5 creatinine 3.0 ? 1.6 2.6 ? 0.87 Day 14 creatinine 3.0 ? 2.1 3.1 ? 1.7 Day 30 creatinine 3.2 ? 2.15 2.9 ? 1 .7 Butler J et al. Nephrol Dial Transplant. 2004;19:391Effect of Nesiritide on Serum Creatinine: VMAC In the VMAC trial, mean changes in serum creatinine obtained at the various time points were similar for nesiritide and IV nitroglycerin (both added to standard of care) for all patients. Nesiritide (n = 273) Nitroglycerin (n = 219) Baseline creatinine (mg/dL) Mean ? SD 1.6 ? 1.06 1.6 ? 0.99 Range 0.4�11.1 0.5 � 9.5 Change from baseline (mg/dL) Day 2 0 ? 0.41 0 ? 0.31 Day 5 +0.1 ? 0.59 0 ? 0.42 Day 14 +0.2 ? 0.85 +0.2 ? 0.6 Day 30 +0.1 ? 0.75 +0.1 ? 0.73 Subanalysis of patients with renal insufficiency (serum creatinine ?2.0 mg/dL), including those requiring chronic dialysis was conducted. Mean serum creatinine for nesiritide and IV nitroglycerin were also similar. Nesiritide (n = 60) Nitroglycerin (n = 44) Baseline creatinine (mg/dL) 3.0 ? 1.5 3.0 ? 1.4 Day 2 creatinine 2.9 ? 1.6 2.8 ? 1.4 Day 5 creatinine 3.0 ? 1.6 2.6 ? 0.87 Day 14 creatinine 3.0 ? 2.1 3.1 ? 1.7 Day 30 creatinine 3.2 ? 2.15 2.9 ? 1 .7 Butler J et al. Nephrol Dial Transplant. 2004;19:391

54. Acute Decompensated Heart Failure:Nesiritide and Mortality No short-term therapy for ADHF has been proven to improve short- or long-term mortality rates. Nesiritide is the only approved ADHF therapy which has been shown in large, randomized trials to provide both significant symptomatic and hemodynamic improvement when added to standard care. Nesiritide has not been studied in a trial powered to evaluate an effect on mortality. Follow dosing instructions and patient exclusion criteria carefully

55. Other last-ditch options Cardiac resynchronization therapy (CRT) Biventricular pacing ICD placement In about 30% of patients with heart failure, an intraventricular conduction delay causes the ventricles to beat asynchronously. This may cause segments of the heart to contract at different times resulting in worsening mitral regurgitation, increased systolic ejection time, and a subsequent decrease in diastolic filling time. CRT uses a specialized pacemaker to re-coordinate the action of the right and left ventricles by pacing them simultaneously � which is why it is also known as biventricular pacing. In about 30% of patients with heart failure, an intraventricular conduction delay causes the ventricles to beat asynchronously. This may cause segments of the heart to contract at different times resulting in worsening mitral regurgitation, increased systolic ejection time, and a subsequent decrease in diastolic filling time. CRT uses a specialized pacemaker to re-coordinate the action of the right and left ventricles by pacing them simultaneously � which is why it is also known as biventricular pacing.

56. Previously, only NYHA class III and IV patients were thought to be candidates for CRT, but recent studies are starting to show some benefits in class I and II patients. Although no improvement in mortality has been shown yet, some secondary outcomes are encouraging � for example, longer time to first hospitalization.Previously, only NYHA class III and IV patients were thought to be candidates for CRT, but recent studies are starting to show some benefits in class I and II patients. Although no improvement in mortality has been shown yet, some secondary outcomes are encouraging � for example, longer time to first hospitalization.

57. Prophylactic ICD devices, either alone or in conjunction with biventricular pacing, are used in high risk heart failure patients to protect against sudden cardiac death as a result of a fatal arrhythmia.Prophylactic ICD devices, either alone or in conjunction with biventricular pacing, are used in high risk heart failure patients to protect against sudden cardiac death as a result of a fatal arrhythmia.

58. The MADIT II trial, published in 2002, demonstrated a clear mortality benefit of ICDs in heart failure patients with ischemic and non-ischemic heart disease.The MADIT II trial, published in 2002, demonstrated a clear mortality benefit of ICDs in heart failure patients with ischemic and non-ischemic heart disease.

59. When to hospitalize? Severely decompensated CHF � hypotension, AMS, ? renal function Dyspnea at rest, O2 sat < 90% Hemodynamically significant arrhythmia New onset atrial fibrillation Acute coronary syndrome Comorbid conditions � PE, DKA, CVA

61. QUESTIONS?