Heart Failure (HF): Scope of the Problem. Temporal Trends in Age-Adjusted Survival After HF Diagnosis. More malignant than cancer

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1 Patients in US (millions) Heart Failure (HF): Scope of the Problem US prevalence*: 5.8 million US annual incidence: 67, Annual mortality: 282, % depending on severity Cost: $39.2 billion 53% of cost due to hospitalization % HF increases with age Hospital discharges for heart failure by sex in United States: and Projected Go A S et al. Circulation. 213;127:e6-e245 Heidenreich P, et al. Circ Heart Fail s 6 s 7 s >8 AHA Statistical Update. Circulation. 21;121:e46-e2. Croft JB et al. J Am Geriatr Soc. 1997;45: Rich M. J Am Geriatric Soc. 1997;45: Temporal Trends in Age-Adjusted Survival After HF Diagnosis More malignant than cancer Women Men Men Women Levy D, et al. N Engl J Med. 22;347: Projected Costs of Heart Failure Care Heart Failure Definition 8% of costs related to hospitalization Pathophysiology: The inability to provide adequate cardiac output to the body at rest or with exertion, or to do so only in the setting of elevated cardiac filling pressures. -E. Braunwald modified by B. Borlaug and M. Redfield Clinically: A clinical syndrome characterized by breathlessness, fatigue and edema caused by an abnormality of the heart Heidenreich P, et al. Circ Heart Fail. 213.

2 Heart Failure Symptoms The Two Faces of Heart Failure Dyspnea Orthopnea Number of pillows Cough GI Effects Nausea, early satiety Fatigue Reduced perfusion to skeletal muscles Peripheral edema CNS effects Confusion, hallucinations Extremity effects Cool extremities Urinary effects Polyuria, nocturia HFrEF HFpEF Heart Failure with Preserved Ejection Fraction (HFpEF) accounts for up to Half of Heart Failure OPTIMIZE-HF Registry, N=41,267 HFrEF HFpEF Fonarow G et al. JACC. 27; 5: % Similar Signs and Symptoms in Patients with HFpEF and HFrEF Edema PND Rest dyspnea S 3 Crackles JVP >6 cm HFrEF HFpEF Orthopnea Cardiomegaly CHARM Investigators Chlorothiazide induced diuresis in a patient with CHF Treatment of Heart Failure Empiric and Evidence-Based

3 Neurohormonal Activation in Heart Failure Pathophysiology Plasma Plasma Renin Norepinephrine Activity (pg/ml) (ng/ml/h) 6 12 Arginine Vasopressin (pg/ml) Atrial Natriuretic Peptide (pg/ml) 3 8 Endothelin-1 (pg/ml) Myocardial injury Left ventricular systolic dysfunction Levels NL HF NL HF NL HF NL HF NL HF Adapted from Cohn JN. Cardiology. 1997;88(suppl 2):2 6 Systemic vasoconstriction Renal sodium and water retention Perceived reduction in circulating volume and pressure Neurohumoral activation SNS RAAS ET, AVP etc ( Natriuretic peptides) Effect of ACE inhibition in patients with CHF Mortality, % CONSENSUS* NYHA Class IV (n = 126) *Risk reduction 4% (P =.3). Risk reduction 16% (P =.36). (n = 126) SOLVD Treatment NYHA Class II III (n = 1284) (n = 1285) Months Swedberg K et al for the CONSENSUS Trial Study Group. Circulation. 199;82: The SOLVD Investigators. N Engl J Med. 1991;325: ACCF/AHA Guideline for the Management of Heart Failure ACE Inhibitors Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Captopril Capoten 6.25 mg tid 5 mg tid mg/day Vasotec 2.5 mg bid 1 mg bid 16.6 mg/day Fosinopril Monopril 5-1 mg qd 8 mg qd N/A Lisinopril Zestril, Prinivil mg qd 2 mg qd 4.5 mg/day, 33.2 mg/day* Quinapril Accupril 5 mg bid 8 mg qd N/A Ramipril Altace mg qd 1 mg qd N/A Trandolapril Mavik 1 mg qd 4 mg qd N/A *No mortality difference between high and low dose groups, but 12% lower risk of death or hospitalization in high dose group vs. low dose group. Is an ARB better than an ACE inhibitor? Losartan Heart Failure Survival Study: ELITE II Primary Endpoint All-Cause Mortality Liver Angiotensinogen Renin DRI Probability of survival 1. Corticosteroids MR MRA Aldosterone K + ACTH Adrenal gland Kidney β-blocker Chymase Angiotensin I Angiotensin II AT 1 R BK Breakdown products ARB DRI, direct renin inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; K + potassium ion; ACE, angiotensin converting enzyme; ACTH, adrenocorticotropic hormone (corticotropin); BK, bradykinin; AT 1R, angiotensin II type 1 receptor; MR, mineralcorticoid receptor ACE ACE inhibitor Captopril, (n=74), 25 events Losartan, (n=78), 28 events Losartan/captopril Hazard Ratio (95% CI): 1.13 (.95, 1.35) P= Days of follow-up Pitt et al Lancet. 2; 355: 82-7.

4 ARBs Class I: ARBs are Class IIb: Addition of an ARB recommended in patients with may be considered in HFrEF with current or prior persistently symptomatic symptoms who are ACEI patients with HFrEF who are intolerant, unless already being treated with an contraindicated, to reduce ACEI and a β-blocker in whom morbidity and mortality an aldosterone antagonist is The use of ARBs to reduce morbidity not and indicated mortality tolerated is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to Level ACE of inhibitors Evidence because = A of cough Level or angioedema of Evidence = (IA) A Routine combined use of an ACEI, ARB, and aldosterone receptor antagonist is potentially harmful for patients with HFrEF. Level of Evidence = C ARBs: Doses Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Candesartan Atacand 4 8 mg QD 32 mg QD 24 mg/day Losartan Cozaar mg QD NOT a class effect, target doses used in clinical trials. 5 mg QD 129 mg/day Valsartan Diovan 4 mg BID 16 mg BID 254 mg/day Circulation 213;128:e Beta-blockers are the most evidencebased therapy in heart failure MERIT-HF CIBIS-2 ACCF/AHA Guideline for the Management of Heart Failure Beta Blockers Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Bisoprolol Zebeta 1.25 mg qd 1 mg qd 8.6 mg/day Carvedilol Coreg mg bid 25 mg bid 37 mg/day Carvedilol Coreg CR 1 mg qd 8 mg qd COPERNICUS SENIORS Metoprolol succinate CR/XL Toprol XL mg qd 2 mg qd 9 mg/day Clinical Tidbits: ACEI first, to low doses β-blocker at LOW dose; titrate to target or maximum tolerated dose Go back to titrate ACEI to target dose The stunning success of ACE inhibitors and beta blockers in mild-moderate HF 1 year mortality (%) Diuretic/ digoxin SOLVD-T Diuretic/ digoxin 13.2 Diuretic/ digoxin CIBIS Diuretic/ digoxin Beta-blocker Corticosteroids MR MRA Is aldosterone (mineralocorticoid) antagonism beneficial in HF? Aldosterone Liver K + ACTH Adrenal gland Kidney β-blocker Angiotensinogen Chymase Renin Angiotensin I Angiotensin II AT 1 R BK ARB DRI Breakdown products DRI, direct renin inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; K + potassium ion; ACE, angiotensin converting enzyme; ACTH, adrenocorticotropic hormone (corticotropin); BK, bradykinin; AT 1R, angiotensin II type 1 receptor; MR, mineralcorticoid receptor ACE ACE inhibitor

5 Trials comparing an aldosterone/mr antagonist to placebo (added to an ACE inhibitor) in systolic HF Probability of survival RALES 1663 NYHA class III/IV patients 95% ACE-I/1% β-blocker Spironolactone.5 RRR (95% CI) 3 (18-4)% P < Years from randomization Probability of survival EMPHASIS-HF 2737 NYHA class II patients 93% ACE-I or ARB/87% β-blocker Eplerenone.5 RRR (95% CI) 22 (5-36)% P = Years from randomization Pitt B, et al. N Engl J Med. 1999;341: Zannad F, et al. N Engl J Med. 21;364: Aldosterone Receptor Antagonists (ARAs or MRAs): ACCF/AHA Guidelines Aldosterone receptor Aldosterone receptor antagonists are antagonists (or MRAs) are recommended to reduce recommended in patients morbidity and mortality after with NYHA class II IV and an acute MI in patients who who have LVEF of 35% or have LVEF of 4% or less less, unless who develop symptoms of contraindicated, to reduce HF or who have a history of morbidity and mortality. diabetes mellitus, unless contraindicated. Strength of Evidence = A Strength of Evidence = B Circulation 213;128:e Aldosterone Antagonists: Doses MRAs: Contraindications Generic Name Trade Name Initial Daily Dose Spironolactone Aldactone mg qd Target Dose Mean Dose in Clinical Trials 25 mg qd 26 mg/day Eplerenone Inspra 25 mg qd 5 mg qd 42.6 mg/day Not recommended when: creatinine is > 2.5 mg/dl (or creatinine clearance is < 3 ml/minute) or serum potassium is > 5. mmol/l Level of Evidence = A Circulation 213;128:e A-HeFT All-Cause Mortality Taylor AL. N Engl J Med 24;351: Reprinted with permission from Massachusetts Medical Society. (Hydralazine/isosorbide dinitrate) Hydralazine and Isosorbide Dinitrate Class I: The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for patients selfdescribed as African Americans with NYHA class III IV HFrEF receiving optimal therapy with ACEIs and β-blockers, unless contraindicated Level of Evidence = A Circulation 213;128:e Class IIa: A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACEI or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated Level of Evidence = B

6 ICD Therapy in HF: MADIT-II and SCD-HeFT Biventricular/multi-site pacing or cardiac resynchronization therapy A B C Moss et al, New Engl J Med 22 Bardy et al, New Engl J Med 25 CRT Improves Synchrony and Reverses Adverse Remodeling Cumulative benefit of poly-pharmacy (and CRT) in severe HF 1 year mortality (%) RALES COPERNICUS CARE-HF Baseline 12 months CRT Aldo. antag. Aldo. antag. Aldo. antag Beta-blocker Aldo. antag Beta-blocker Aldo. antag Beta-blocker CRT Heart Failure with Preserved Ejection Fraction (HFpEF) accounts for up to Half of Heart Failure Outcomes Trials in HFpEF OPTIMIZE-HF Registry, N=41,267 CHARM-Preserved PEP-CHF HFrEF HFpEF I-PRESERVE TOPCAT Fonarow G et al. JACC. 27; 5:

7 TOPCAT: 1 Outcome (CV Death, HF Hosp, or Resuscitated Cardiac Arrest) TOPCAT: Heart Failure Hospitalizations Spironolactone HR =.89 ( ) p= /1723 (2.4%) 32/1722 (18.6%) Total HF Hosp Spiro : 394 : 475 P<.1* 245/1723 (14.2%) 26/1722 (12.%) Spironolactone HR =.83 (.69.99) p=.42 *poisson regression Exploratory (post-hoc): vs. Spiro by region US, Canada, Argentina, Brazil HR=.82 ( ) : 28/881 (31.8%) 216 Update Interaction p=.122 Russia, Rep Georgia HR=1.1 ( ) : 71/842 (8.4%) No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFpEF. Diuretics are used to control sodium and water retention and relieve breathlessness and edema as in HFrEF. Adequate treatment of hypertension and myocardial ischemia is also considered to be important Sinus node inhibition with Ivabradine MOA: Blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the sinoatrial node, responsible for the I f current Delays diastolic depolarization Does not affect other ion channels Does not alter myocardial contractility and intra-cardiac conduction SHIFT Study Design Patients > 18 years old NSR & HR 7 bpm NYHA FC II-IV and stable on meds for 4 wks LVEF 35% On target or maximally tolerated doses of BB Hospitalization for worsening HF in 12 mo 14 day run-in N=6558 Ivabradine 5mg BID x 2 weeks, then 7.5mg BID N=3268 BID N=329 Median f/u duration 22.9 months Swedberg K. Lancet. 21;376(9744):

8 HN O HO O OH O O N N N N O OH NH SHIFT Study Results Number of Events Outcome Ivabradine HR (95% CI) ARR CV Death or HF Hospitalization (.75,.9) 4.2% CV Death (.8, 1.3) 1.1% HF Hospitalization (.66,.83) 4.7% The treatment effect reflected only a reduction in the risk of hospitalization for worsening HF; there was no benefit observed for the mortality component of the primary endpoint Adverse Drug Reactions with Rates 1% on Ivabradine versus Adverse Reaction Ivabradine N=326 N=3278 Bradycardia 1% 2.2% Hypertension 8.9% 7.8% Atrial Fibrillation 8.3% 6.6% Phosphenes (visual brightness)* 2.8%.5% *inhibition of the retinal current I h, responsible for curtailing retinal responses to bright light stimuli. Most pronounced under triggering circumstances (rapid changes in brightness) Swedberg K. Lancet. 21;376(9744): Swedberg K. Lancet. 21;376(9744): Ivabradine Considerations Indication: To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF LVEF 35% In sinus rhythm with resting heart rate 7 beats/minute Either on maximally tolerated doses of β-blockers or have a contraindication to β-blocker use Doses: Starting dose 5 mg twice daily, up to 7.5mg twice daily 216 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 213 ACCF/AHA Guideline for the Management of Heart Failure Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 7 bpm or greater at rest (IIa, B-R) Only 25% of patients studied in SHIFT were on optimal doses of beta-blocker therapy. It is important to initiate and up titrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of ivabradine initiation A first-in-class Angiotensin Receptor Neprilysin Inhibitor Simultaneously Inhibits NEP and the RAS PARADIGM-HF: Study Design Vasoactive Peptide System pro-bnp Heart Failure Renin Angiotensin System Angiotensinogen (liver secretion) Randomization (N = 8442 patients) Single-blind run-in period Double-blind randomized treatment period 2 mg bid ANP BNP CNP Adrenomedullin Bradykinin Substance P (angiotensin II) Vasodilation blood pressure sympathetic tone aldosterone levels fibrosis hypertrophy Neprilysin Natriuresis/Diuresis NT-pro BNP Sacubitril (AHU377) LBQ657 Inactive fragments X is a novel crystalline complex consisting of the molecular moieties of valsartan and sacubitril in an equimolar ratio Valsartan X Angiotensin I Angiotensin II AT 1 receptor Vasoconstriction blood pressure sympathetic tone aldosterone fibrosis hypertrophy 1 mg bid 1 mg bid Testing tolerability to target doses of enalapril and 2 mg bid 1 mg bid On top of standard heart failure therapy (excluding ACEIs and ARBs) 2 weeks 1-2 weeks 2-4 weeks ~ 21 to 43 months (event-driven) 5 mg bid for 1-2 weeks followed by enalapril 1 mg bid as an optional starting run-in dose for those pts who are treated with ARBs or with low dose of ACEI Primary outcome: CV death or heart failure hospitalization (event driven: 2,41 patients with primary events)

9 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Patients at Risk (n=4212) (n=4187) HR =.8 ( ) 8 P =.4 Number needed to treat = Days After Randomization McMurray et al. NEJM Cardiovascular Death Kaplan-Meier Estimate of Cumulative Rates (%) HR =.8 ( ) P =.8 Number need to treat = 32 (n=4212) (n=4187) Days After Randomization Patients at Risk McMurray et al. NEJM vs on Primary Endpoint and on Cardiovascular Death, by Subgroups Primary endpoint McMurray et al. NEJM 214 Cardiovascular death PARADIGM-HF: All-Cause Mortality Kaplan-Meier Estimate of Cumulative Rates (%) HR =.84 ( ) P<.1 McMurray et al. NEJM 214 (n=4212) (n=4187) Days After Randomization Patients at Risk PARADIGM-HF: Adverse Events Prospectively identified adverse events (n=4187) (n=4212) P Value Symptomatic hypotension <.1 Serum potassium > 6. mmol/l Serum creatinine > 2.5 mg/dl Cough <.1 Discontinuation for adverse event Discontinuation for hypotension NS Discontinuation for hyperkalemia 11 NS Discontinuation for renal impairment Angioedema (adjudicated) McMurray et al. NEJM 214 Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise ---- Early Benefit of Months after Randomization Packer et al. Circulation 214

10 PARADIGM-HF: Mode of Death Number HR p = All causes CV causes Sudden Worsening HF < Desai et al. Eur Heart J (%) PARADIGM-HF: Hospitalization for heart failure Proportion of patients HR.79 (.71,.89) p <.1 Patients hospitalized Packer et al. Circulation 214 Number of admissions* RR.77 (.67,.89) p =.4 Hospitalizations *Includes repeat episodes NT pro BNP and BNP Cardiomyocyte Blood Mechanism: NT-proBNP and BNP Sacubitril/Valsartan Considerations NT-proBNP NT-proBNP remains an accurate measure of 1 severity of HF in the setting of treatment with but BNP 2 will not 4 be reliable! 6 8 Pre Run-in Baseline NT-proBNP BNP Months BNP McMurray et al. NEJM 214 Indication: To reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic heart failure (NYHA class II IV) and reduced ejection fraction Used in place of ACEI or ARB Doses: 24/26 mg, 49/51 mg, 97/13 mg Starting dose 49/51 mg twice daily for patients previously on ACEI or ARB, 24/26 mg for low dose ACEI/ARB (</= 1mg enalapril daily) or ACEI/ARB naive MUST have 36 hours washout between ACEI dose and sacubitril/valsartan initiation

11 216 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 213 ACCF/AHA Guideline for the Management of Heart Failure The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A), OR ARBs (Level of Evidence: A), OR ARNI (Level of Evidence: B-R) in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HFrEF to reduce morbidity and mortality 216 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality (IA) The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE inhibitors because of cough or angioedema (IA) In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality (IB-R) ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor (IIIB-R) PARAMOUNT: Significant Reduction in NT-proBNP with at 12 Weeks NTproBNP (pg/ml) Solomon et al. Lancet (733,112) 835 (71, 981) 783 (67,914) p = Weeks Post Randomization Valsartan /Valsartan:.77 (.64,.92) P =.5 65 (512, 714) Solomon et al. Lancet 212 ESC Hotline 212 PARAGON-HF: Prospective comparison of ARni with Arb Global Outcomes in heart failure with preserved ejection fraction A randomized, double blind, trial to evaluate the long-term efficacy and safety profile of the angiotensin receptor neprilysin inhibitor (ARNI),, compared with valsartan, in patients with heart failure with preserved ejection fraction (HFpEF) Summary Heart failure remains extremely morbid and deadly Current treatment of HFrEF is both empiric (diuretics, lifestyle) and evidenced-based (ACEi, ARBs, Beta-Blockers, MRAs) Devices used for specific subsets (ICD for reduced EF, CRT for reduced EF and wide QRS/LBBB, LVAD for end-stage or bridge to transplant) New Therapies are likely to be approved for use soon based on results of recent clinical trials In HFpEF, current treatment remains empiric, with some evidence that RAAS blockade can be useful in some patients Clinical trials in HFpEF are ongoing with novel agents