Evaluation and Management of Heart Failure

Transcription

1 Evaluation and Management of Heart Failure S. Carolina Masri, MD Division of Cardiology University of Washington Disclosures No financial disclosures No conflict of interest

2 Objectives Frame the epidemiology of HF Discuss evidence-based pharmacotherapies on reduced ejection fraction Explore the utility of guideline directed medical therapies (GDMT) Heart Failure Epidemic in US Population Group Prevalence Incidence Mortality Hospital Discharges Cost Total population 5,700, , , ,000 $39.2 billion At age 40, lifetime risk is 20 % in both genders About 50% HFrEF, 50% preserved Mortality rate 50% within 5 years 1-month readmission rate is ~25 % ACCF/AHA Guidelines

3 Chronic Heart Failure Groups Classification LV EF % Description HFrEF 40 Effective therapies well-established HFpEF 50 Diastolic HF, challenging diagnosis, therapies unclear a. HFpEF, borderline b. HFpEF, improved Intermediate group, clinically more similar to HFpEF > 40 Recovered HFrEF, not well characterized Yancy C et al. ACCF/AHA 2013 Guidelines Heart Failure Progression Annual Survival Rate Survival Rate Hospitalizations I II III IV 1 Hospitalizations / year.1 Deceased NYHA CLASS Adapted from Bristow, MR Management of Heart Failure, Heart Disease: A Textbook of Cardiovascular Medicine, 6th edition, ed. Braunwald et al.

4 Heart Failure Progression New York Heart Association Functional Classification Class I: Class II: Class III: Class IV: No symptoms with ordinary activity Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea, or angina Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest

5 Stages of CHF ACC/AHA Guidelines year survival Prevalence 20% 75% D Refractory C 0.2% 12% Prior or current HF symptoms 97% 96% B Structural heart disease LVH, MI, low LVEF, dilatation, valvular disease A High-risk patients 34% 22% Hypertension, diabetes, coronary disease, family history, cardiotoxic drugs Stage A High risk with no symptoms Stage B Structural heart disease, no symptoms Stage C Structural disease, prior or current symptoms Stage D Refractory symptoms requiring special intervention Stages & steps: treatment of systolic HF Digoxin Aldosterone antagonists CRT, ICD if applicable Sodium restriction, diuretics ACEI, BB in all. Is patient candidate for surgery? ACEI, ARB s if intolerant of ACEI, BB if MI or low LVEF Treat HTN, DM, CAD, dyslipidemia. ACEI or ARB Risk factor reduction, patient and family education Hospice VAD, TX Inotrope Brief inotrope Revised August 2005 from Jessup M, Brozena S. NEJM 2003;348:2003

6 (#1) 75 year old man with non-ischemic CM is admitted to outside hospital. BNP on admission is 500 pg/ml. He is transferred immediately to your institution for further management. NT-proBNP at your hospital the following day is 2300 pg/ml. Which of the following is true? a) His clinical condition has worsened since his initial presentation b) The BNP and NT-proBNP values are approximately Equivalent c) Natriuretic peptide levels are not useful in the elderly d) None of the above Structure and Cleavage of NT-proBNP/BNP T ½ = 2 hours T ½ = 22 minutes Both digested by NEPs and cleared renally

7 NT-ProBNP vs BNP NT-ProBNP values between 5-10 times BNP value in same patient Both are affected by age (NT-ProBNP more) Both affected by renal function BNP and diagnosis of HF: Breathing Not Properly Trial Dyspneic patients in the ED setting ROC for BNP was 0.91, more accurate than H+P findings Cutpoint of 100 pg/ml for all pt: Sensitivity 90%, specificity 76% Maisel et al. N Engl J Med 347: , 2002

8 Conditions that Influence BNP Concentrations Increased BNP Decreased BNP Age (older) Sex (female) Renal dysfunction MI/ACS Right-sided heart failure (corpulmonale, PE) High output failure (cirrhosis,septic shock) Obesity Early acute heart failure (less than 1 hr) Heart Fail Rev 8: , Death or hospitalization after admission stratified by pre-discharge BNP Logeart et al, JACC 2004

9 BNP/NT-proBNP Heart Failure Pathophysiology Myocardial injury (CAD, HTN, CM, Valvular disease) Fall in LV performance wall stress Activation of RAAS, SNS and Cytokines ANP BNP Myocardial Toxicity Peripheral vasoconstriction Hemodynamic alterations Remodeling and Progressive worsening of LV function Morbidity and Mortality Heart Failure symptoms

10 Goals in the Management of Heart Failure Stabilize the patient Make the patient feel better Stabilize the disease process Keep the patient alive, out of the hospital, and feeling better (#2) Ms LA is a 62 year old female with systolic heart failure LVEF 32 % in CF II of NYHA. She becomes an expert on HF management from reading wikipedia. She is wondering which of the following will improve her chance of survival? a) β-blocker, ACE-I, aldosterone antagonists b) β-blocker, ACE-I, aldosterone antagonists, diuretics c) β-blocker, ACE-I, aldosterone antagonists, digoxin d) All of the above e) None of the above

11 Diuretics Used to relieve fluid retention and treat symptoms Diuretics do NOT decrease mortality In fact, observational studies have shown association of higher doses with worse survival Sodium Reabsorption Sites in the Nephron 70% Proximal Tubule 5% Distal Tubule Thiazide Diuretics Glomerulus Loop Diuretics Collecting Tubule 20% Loop of Henle 1-4% Mineralocorticoid Receptor antagonist

12 Bioavailability of Loop Diuretics 100% - 80% - 50% - 10% furosemide torsemide bumetanide Additional points about diuretics 1 mg Bumetanide= 20 mg torsemide = 40 mg furosemide Furosemide PO to IV conversion is 2:1 Bumetanide and torsemide PO to IV conversion are 1:1 Consider ethacrynic acid if true allergy to loop diuretics Sulfa moiety in antibiotics is not the same as loop diuretics

13 Diuretics: Guideline-Based Recommendations Indication Considerations where greater diuresis needed. (Diuretic refractoriness) Monitoring To improve symptoms in fluid overload Increased dose 2 or 3 times daily dosing provides more diuresis Consider switch to oral torsemide/bumetanide if persistent fluid retention despite high dose of furosemide Consider adding chlorothiazides or metolazone. Try to avoid chronic daily metolazone use: high potential for electrolyte imbalance and volume depletion. Intravenous administration BMP, symptomatic hypotension, renal dysfunction, especially with high dose and combination use. When treatment goal achieved Consider dose reduction or even discontinuation if improved clinical status Monitor carefully for recurrent fluid retention. Patient education Weight and fluid monitoring Selected patients may adjust dose to weight / clinical change ACCF/AHA 2013: Common Diuretics Drug Initial Dose Max Dose Duration of Action Loop Diuretics Bumetanide mg 1-2x/d 10 mg 4-6 h Furosemide mg 1-2x/d 600 mg 6-8 h Torsemide mg 1x/d 200 mg h Thiazide Diuretics Hydrochlorothiazide mg 1-2x/d 200 mg 6-12 h Metolazone mg with loop diuretic 20 mg h Chlorothiazide (IV) 500 mg with loop diuretic N/A N/A K-sparing Diuretics Amiloride 5 mg 1x/d 20 mg 24 h Spironolactone mg 1x/d 50 mg 1-3 h Triamterene mg 2x/d 200 mg 7-9 h Adapted from: Yancy C et al. ACCF/AHA 2013 Guidelines

14 (#3)-Your patient Mr G has recently been discharged from the hospital on lisinopril 10 mg bid, furosemide 40 mg qd and low doses of carvedilol 6.25 mg bid. On his visit to the clinic one week after dismissal, he reported feeling well, able to climb 2 flights of stairs, no PND or orthopnea. His weight has been stable, no swollen of LE. VS: BP: 110/60 mmhg, HR: 78 bpm,reg rhytm PE: No JVD, no gallop, CTA bilaterally, no peripheral edema, warm and well perfused. Normal mentation Labs: Creatinine: 1.7 mg/dl ( prior to discharged was 1.3 mg/dl) K: 4.9 meq/l BNP: 250 pg/ml upon admission was 1040 pg/ml (#3)-Cont d The most appropriate step at this point include which of the following? a)discontinue treatment with lisinopril and start with hydralazine/isosorbide dinitrate. b)discontinue treatment with lisinopril and start with candesartan c)decrease the doses to half of lisinopril d)continues with the same treatment

15 RAAS Pathway: ACE-I Angiotensinogen Renin Non-ACE pathways (eg, chymase) Angiotensin I ACE Angiotensin II Vasoconstriction Cell growth Na/H 2 O retention Sympathetic activation AT 1 Aldosterone AT 2 Cough, angioedema Benefits? Bradykinin Inactive fragments Vasodilation Antiproliferation (kinins) ACEI in Chronic Heart Failure JAMA 1995;273:1450 Metanalysis - ACEi trials in Heart Failure N~7,500 patients Death 23% Death/HF Hosp 35% Heart Failure Death 31% Sudden Death 9% Reinfarction 18%

16 Selected ACE-I Trials: Mortality CONSENSUS SOLVD Treatment SOLVD Prevention VHeFT II ATLAS N LVEF Not reported < 35% < 35% < 45% < 30% NYHA IV II-IV I I-IV II-IV ACE-I Enalapril Enalapril Enalapril Enalapril Lisinopril mg Mortality in comparator 36% in placebo arm at 12 mo 40% in placebo arm at 41 mo 16% in placebo arm at 37 mo 25% in HYD/NIT arm at 24 mo 42% in Lisinopril mg at 46 mo RRR 31% 16% No difference 28% No difference Adapted from: Griffin BP et al. Cleveland Clinic Cardiology Board Review Class I * Benefit for hospitalization Trend for ACM; Low background mortality; 12 year f/u significant ACE-I vs. ISDN/Hydra Low vs. High dose When to Use ACE Inhibitors? All HF patients with LVEF <40% should be treated with an ACE-I and a beta-blocker, unless a specific contraindication exists (Class I, Level A) Jessup et al, Circulation 2009

17 Optimal Dosing of ACE Inhibitors General Guideline: Start low and titrate to the target dose used in the clinical trials or the MAXIMUM TOLERATED DOSE (ATLAS trial) Captopril mg 50 mg BID-TID (SAVE) Enalapril 2.5 mg BID 20 mg BID (SOLVD/X) Ramipril 2.5 mg BID 5 mg BID (AIRE/EX) Lisinopril mg QD mg OD (GISSI 3) Trandolapril 1mg 4 mg (TRACE) ACE Pearls Up to 85-90% tolerate ACEIs Start with low dose, especially in elderly Follow-up BMP in 1-2 weeks Titrate/double dose to target every 1-2 weeks Bedtime dosing once BB introduced Most ACEIs now on $ 4 generic lists Remember some ACE inhibitor is better than no ACE inhibitor

18 ACEI or ARB - pearls Worsening renal function 10% to 30% creatinine can be anticipated with ACE - and it is not an indication to discontinue treatment: Avoid sodium and volume depletion Reduce diuretic dose Fluid resuscitation, salt liberalization Avoid NSAIDs Hyperkalemia Incidence ~ 3-10%, [K+] > 5.5 meq/l Drug Interactions: NSAIDs, KCL supplements, Additional considerations: ACE-I ACE-I can cause angioedema Bilateral RAS is a contraindication to ACE-I AVOID during pregnancy Can increase bradykinin, resulting in cough Generally used as 1 st line therapy due to vasodilation even during ADHF Inability to tolerate ACE-I is a bad prognostic sign

19 RAAS Pathway: ARB Angiotensinogen Renin Non-ACE pathways (eg, chymase) Angiotensin I ACE Angiotensin II Vasoconstriction Cell growth Na/H 2 O retention Sympathetic activation AT 1 Aldosterone AT 2 Cough, angioedema Benefits? Bradykinin Inactive fragments Vasodilation Antiproliferation (kinins) ARB in Heart Failure Questions Alternative to ACEI? Better than ACEI? Added to ACEI?

20 CHARM-Alternative: ARB vs. Placebo Primary outcome of CV death or CHF hospitalization 50 Proportion With CV Death or CHF Hospitalization (%) Placebo Candesartan (intolerant of ACE-I) HR 0.77 (95% CI ), P=.0004 Adjusted HR 0.70, P< Number at risk Candesartan 1, Years Placebo 1, (40.0%) 334 (33.0%) Granger CB, et al. Lancet. 2003;362: ARB vs. ACE-I No clear difference between ACE-I and ARB, with some trials favoring ARB, and others trending toward ACE-I superiority ARB in addition to ACE-I ARB added to ACE-I had no impact on all-cause mortality in any of the major cardiovascular trials

21 ACEI/ARBs : Low vs Higher doses Higher doses HF hospitalizations > Death ATLAS - Lisinopril 5 vs 35 mg 24% vs. 8% HEAAL - Losartan 50 vs 150 mg 13% vs 6% ARBs Doses in HF ARBs Starting HF doses! Target HF doses! Mean doses achieved in trials! Candesartan 4-8 mg qd 32 mg qd 24 mg/day Losartan mg qd 150 mg qd 129 mg/day Valsartan mg bid 160 mg bid 254 mg/day Mineralocorticoids receptors antagonist Direct aldosterone antagonism in LV remodeling: Decreased local fibrosis Increased local dilation via increased NO Decrease cardiac NE release, SCD Benefits in 1-3 months

22 MRAs Beneficial in HFrEF and Post-MI LVD Probability of Survival RALES (Severe HFrEF) 30% Risk Reduction 15% Risk Reduction Placebo Spironolactone EPHESUS (Post-MI) Placebo Epleronone 0.50 RR = 0.70 RR = RR = 0.78 P < P < P = Months Months Months Pitt NEJM 1999 Pitt NEJM 2003 Zannad NEJM EMPHASIS (Mild HFrEF) 22% Risk Reduction Epleronone Placebo Reviews of Mechanisms : Pitt Heart Fail Rev 2012; Kamalov,,Weber JCV Pharm 2013 When to use aldosterone blockers? ACCF/AHA 2013: -Recommended for NYHA class II-IV HF with LVEF 35%. -After acute MI with LVEF 40% or history of diabetes Contraindications SCr > 2.5 men, SCr > 2.0 women (egfr < 30 ml/min) Acute renal insufficiency Hyperkalemia, K+ > 5

23 Aldosterone Blockers Pearls Decrease mortality by 15-30% Start low spiro/eplerenone mg/day. Target doses mg/day. Follow-up BMP after initiation, dose change: 3 days then, 1 week then, monthly for 3 months then, Every 3 months indefinitely Eplerenone is generic $28/month at UWMC Pharmacy Less Gynecomastia 1% vs. 10% Less impotence (#4)You are asked to evaluate a 60 year old woman AA who is admitted for treatment of cellulitis. She is doing well, but nurses has been refusing to administer her lisinopril and carvedilol due to low blood pressure. She has stable NYHA Class II symptoms. She is not lightheadedness. Her BP usually range of 75/50-80/55 mmhg. Her LVEF is 28 %. Meds: Lisinopril 20 mg qd, Carvedilol 12.5 mg bid, furosemide 20 mg qd, Spironolactone 12.5 mg qd VS: BP: 80/50 HR : 66 bpm regular PE: No JVD, no gallop, CTA bilaterally, no peripheral edema, warm and well perfused. Normal mentation

24 (#4)-Cont d Which one of the following represent the most appropriate next step? a)hold the lisinopril and carvedilol completely b)reduce the doses of lisinopril and carvedilol by half and follow up with the cardiologist as outpatient c)discontinue lisinopril and start hydralazine/isordil d)continues same doses of lisinopril and carvedilol How Do Beta Blockers Improve Heart Failure? Reverse LV remodeling, adrenergic receptors Reduces risk of sudden cardiac death Benefits in 3-6 months Contraindications: Severe bronchospastic disease Severe, unpaced, symptomatic bradycardia HR < 50 Unpaced 2nd or 3rd degree AV Block

25 Effect of Beta Blockade on Outcome in Patients With HF and Post-MI LVD BB in HFrEF Drug Starting HF Doses Target HF Doses Mean Dose Achieved in Trials Bisoprolol 1.25 mg qd 10 mg qd 8.6 mg/day Carvedilol mg bid (with food) 25 mg bid (<85 kg) 50 mg bid (>85 kg) 37 mg/day Carvedilol CR 10 mg qd 80 mg qd n/a Metoprolol Succinate CR/XL mg qd 200 mg qd 159 mg/day

26 BB -Recommendations General Recommended for symptomatic and asymptomatic patients with reduced LVEF ( 40%) to reduce M&M. Initiation; Dosing; Initiate at low doses Up-titrate gradually, generally 2 week intervals Target doses shown to be effective in clinical trials Target dose in 8-12 wks; Maintain at maximum tolerated dose Beta Blockers -Pearls If symptoms worsen or side effects appear If an acute exacerbation of chronic HF occurs Following decompensation Adjust dose of diuretic Continue titration to target dose once symptoms at baseline. Maintain therapy if possible. Reduce dosage if necessary. Avoid abrupt discontinuation. If discontinued or reduced, reinstate gradually before discharge Initiate after optimizing volume status and discontinuation of intravenous inotropic agents. Whenever possible, initiate prior to hospital discharge in stable patients.

27 Should we increase ACE-/ARB to target doses before beginning BB? Titrating to target doses provides more benefit than very low doses. However, the difference in efficacy between intermediate and high doses is small. Thus, not unreasonable to start β-blockers after intermediate doses of ACEI are achieved, or vice versa. Do not reduce or discontinue ACEI or β-blockers for asymptomatic low BP measurement Hydralazine and Nitrates Rationale is to reduce preload and afterload by both venous and arterial vasodilation Hydralazine is predominately an arterial vasodilator Nitrates are mostly venodilators Increases NO bioavailability since nitrates are NO donors and hydralazine may have antioxidant effects

28 What about Hydralazine and Isordil? The A-HeFT Trial 1050 NYHA III/IV AA pts LVEF < 35% Composite endpt (death, HF hosp, QOL), Terminated early Hyd 75/Isordil 40 TID Mean - Hyd 142/Isordil 76 ACE/ARB 86% BB 74% Spiro 39% Digoxin 59% Survival % % Decrease in Mortality Fixed Dose ISDN/HDZN Placebo P = Days Since Baseline Visit Mortality 43%, p=0.02 Do non-black patients benefit from hydralizine/nitrates? Ann Taylor et al.nejm 2004;351: Hydralazine-Nitrate Combination - Guideline-Based Recommendations

29 Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs GDMT RR Reduction in Mortality NNT for Mortality Reduction (Standardized to 36 mo) RR Reduction in HF Hospitalizations ACE - or ARB 17% 26 31% Beta blocker 34% 9 41% Aldosterone antagonist 30% 6 35% Hydralazine/nitrate 43% 7 33% Pharmacotherapy: Digoxin The oldest cardiac drug still in contemporary use Inhibits Na-K ATPase increases contractility Neurohormonal effects decreased SNS activation, vagomimetic Slows AV conduction

30 Digoxin: DIG Trial (NEJM 1997) Reduces hospitalization But does NOT reduce mortality Narrow therapeutic window : Digoxin level should be < 1.0 (0.5 to 0.9) ng/ml Monitor closely for digoxin toxicity Renewed interest in certain subgroups? Subanalyses suggest that sicker patients may have additional benefit (EF < 25%, NYHA III-IV) Vincent van Gogh s yellow period and digitalis Starry night Dr. Gachet at a Table with Sprig of Foxglove

31 Digoxin Toxicity Symptoms: Fatigue, anorexia, diarrhea, yellow halos, confusion, agitation Classic arrhythmias seen with toxicity: - Paroxysmal atrial tachycardia w/ block - Accelerated junctional rhythm - Bidirectional ventricular tachycardia (only dig and CPVT can do this) Electrolyte abnormalities that predispose to dig tox: - Low Mg, Low K, High Ca PARADIGM HF Valsartan-LCZ696 NEJM 2014

32 PARADIGM HF Valsartan-LCZ696 NEJM 2014 Enalapril 10 mg BID vs. Valsartan-Neprilysin 200 mg BID in 8442 patients NYHA 2-4, EF 35%, BNP >150 or >100 if HF Hospitalization <12 months. On ACEI/ARB with SBP 100 and egfr>30. F/U 27 months Composite 20% CV death 20% HF Hosp 21% Mortality 16% First medication to replace a HF medication (ACEI) Evidence-Based Treatment for Heart Failure with Reduced LVEF ACEI or ARB ICD* Reduce Mortality -Blocker CRT an ICD* Aldosterone Antagonist Hyd/ISDN* Control Volume Sodium Restriction* Diuretics* Treat Residual Symptoms Digoxin* Enhance Adherence Education Disease Management Performance Improvement Systems *For select indicated patients. Treat Comorbidities Aspirin* Warfarin* Statin* 18

33 Potential Impact of Optimal Implementation of Evidence-Based HF Therapies on Mortality Guideline Recommended HF Patient Current HF Potential Lives Therapy Population Eligible Population Saved per Year for Treatment, n* Eligible and Untreated, n (%) ACEI/ARB 2,459, ,767 (20.4) 6516 Beta-blocker 2,512, ,809 (14.4) 12,922 Aldosterone Antagonist 603, ,326 (63.9) 21,407 Hydralazine/Nitrate 150, ,749 (92.7) 6655 CRT 326, ,604 (61.2) 8317 ICD 1,725, ,512 (49.4) 12,179 Total ,996 Fonarow GC, et al. Am Heart J 2011;161: Improved Adherence to ACC/AHA HF Guidelines Translates to Improved Clinical Outcomes in Real World HF Patients Each 10% improvement in ACC/AHA guideline-recommended composite care was associated with a 13% lower odds of 24- month mortality (P<0.0001) Fonarow GC, et al. Circulation. 2011;123:

34 Case# 56 y/o male caucasian admitted in 10/2014 because of AHF. Normal coronary arteries and cardiac MRI without evidence of acute myocarditis and or infiltrative disease Echocardiogram 10/14 Echocardiogram 3/15 Meds: Metoprolol XL 200 mg qd, Lisinopril 20 mg qd, Spironolactone 12.5 mg qd, Now off diuretics Conclusions HF remains common and costly in the current era, with increasing incidence and prevalence Heart failure medications can reduce mortality by 60-70% Effort should be made to implement guidelinerecommended therapies in HF patients in absence of contraindications or intolerance High risk patients Inability to tolerate or need to withdraw HF medications Low BP, Sodium High Diuretic dose, BUN, Creatinine, BNP Recurrent hospitalizations

35 Thank you for your attention!

36 ARB vs. ACE-I ELITE I ELITE II OPTIMAAL VALIANT N Admission criteria Ischemic etiology EF < 40% NYHA II-IV Age > 65 y EF < 40% NYHA II-IV Age > 60 y MI w/ anterior Q waves or clinical HF or EF < 35% or LVEDD > 65 mm EF < 40% or clinical HF 68% 79% 100% post-mi 100% post-mi ARB Losartan Losartan Losartan Valsartan Comparator Captopril Captopril Captopril Captopril Mortality 46% RRR at 12 mo No difference at 18.2 mo No difference at 32.4 mo No difference at 24.7 mo No clear difference between ACE-I and ARB, with some trials favoring ARB, and others trending toward ACE-I superiority Adapted from: Griffin BP et al. Cleveland Clinic Cardiology Board Review ARB in addition to ACE-I ValHEFT CHARM Added VALIANT N LVEF < 40% < 40% < 40% or clinical HF NYHA II-IV II-IV I-IV Ischemic etiology 57% 62% 100% ARB Valsartan Candesartan Valsartan ACE-I use 93% on ACE-I 100% on ACE-I 100% on captopril Mortality No difference at 23 mo No difference at 41 mo No difference at 24.7 mo ARB added to ACE-I had no impact on allcause mortality in any of the major cardiovascular trials Adapted from: Griffin BP et al. Cleveland Clinic Cardiology Board Review

37 Carvedilol vs Metoprolol Succinate Usefulness of Torsemide after Admission for ADHF 234 pts admitted for ADHF Randomized on Discharge torsemide furosemide 52% HF Hospitalization (Murray, et al. Am J Med 2000;111: )

38 DIG Trial (NEJM 1997) Death or HF Hosp HF with EF < 45% on ACE and diuretic N = 6800 Mean EF 28% Mortality Severity of Heart Failure Mode of Death NYHA II CHF NYHA III 64% 12% 24% Other Sudden Death n = % 26% 15% CHF Other Sudden Death NYHA IV CHF n = % 11% 56% Other Sudden Death n = 27 MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353:

39 Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter Maladaptive Mechanisms in Heart Failure Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin Neprilysin inhibition Inactive metabolites