Evidence-Based Approaches to the Management of Heart Failure: Reducing Hospitalization and Improving Patient Outcomes Eldrin F. Lewis, MD, MPH Director of Cardiovascular Clerkship Brigham and Women s Hospital Harvard Medical School Boston, Massachusetts Patients in US (millions) Heart Failure (HF): Scope of the Problem 1 8 6 4 2 3.5 4.8 1. 1991 21 237 US prevalence*: 5.8 million US annual incidence: 67, Annual mortality: 282,754 5-1% depending on severity Cost: $39.2 billion 53% of cost due to hospitalization % HF increases with age 5 s 6 s 7 s >8 AHA Statistical Update. Circulation. 21;121:e46-e2. Croft JB et al. J Am Geriatr Soc. 1997;45:27 275. Rich M. J Am Geriatric Soc. 1997;45:968 974. Hospital discharges for heart failure by sex in United States: 198 21 and Projected Temporal Trends in Age-Adjusted Survival After HF Diagnosis Go A S et al. Circulation. 213;127:e6-e245 Heidenreich P, et al. Circ Heart Fail 213. Men Women Levy D, et al. N Engl J Med. 22;347:1397-142. More malignant than most cancers Projected Costs of Heart Failure Care Women Men 8% of costs related to hospitalization Heidenreich P, et al. Circ Heart Fail. 213. 1
Heart Failure Definition Heart Failure Symptoms 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 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 Neurohormonal Activation in Heart Failure Treatment of Heart Failure Empiric and Evidence-Based Levels Plasma Plasma Renin Norepinephrine Activity (pg/ml) (ng/ml/h) 6 5 4 3 2 1 12 9 6 3 12 Arginine Vasopressin (pg/ml) 6 4 2 Atrial Natriuretic Peptide (pg/ml) 3 25 2 1 5 8 6 4 2 Endothelin-1 (pg/ml) NL HF NL HF NL HF NL HF NL HF Adapted from Cohn JN. Cardiology. 1997;88(suppl 2):2 6 Pathophysiology Effect of ACE inhibition in patients with CHF Systemic vasoconstriction Renal sodium and water retention Myocardial injury Left ventricular systolic dysfunction Perceived reduction in circulating volume and pressure Mortality, % 8 6 4 2 CONSENSUS* NYHA Class IV (n = 126) (n = 126) SOLVD Treatment NYHA Class II III (n = 1284) (n = 1285) Neurohormonal activation SNS RAAS ET, AVP etc Natriuretic peptides 6 12 18 24 3 36 42 48 *Risk reduction 4% (P =.3). Months Risk reduction 16% (P =.36). Swedberg K et al for the CONSENSUS Trial Study Group. Circulation. 199;82:173 1736. The SOLVD Investigators. N Engl J Med. 1991;325:293 32. 2
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 122.7 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 2.5-5 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 1.25-2.5 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. Losartan Heart Failure Survival Study: ELITE II Primary Endpoint All-Cause Mortality Probability of survival 1..8.6.4.2 Captopril, (n=74), 25 events Losartan, (n=78), 28 events Losartan/captopril Hazard Ratio (95% CI): 1.13 (.95, 1.35) P=.16. 1 2 3 4 5 6 7 Days of follow-up Pitt et al Lancet. 2; 355: 82-7. ARBs Class I: ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACEI intolerant, unless contraindicated, to reduce morbidity and mortality Level of Evidence = A Class IIb: Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are already being treated with an ACEI and a β-blocker in whom an aldosterone antagonist is not indicated or tolerated Level of Evidence = 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 12.5 25 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:e24-327. Beta-blockers are the most evidencebased therapy in heart failure MERIT-HF CIBIS-2 Have we pushed inhibiting the RAAS as far as we could go? COPERNICUS SENIORS 3
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 3.125 mg bid 25 mg bid 37 mg/day Carvedilol Coreg CR 1 mg qd 8 mg qd Metoprolol succinate CR/XL Toprol XL 12.5-25 mg qd 2 mg qd 9 mg/day The stunning success of ACE inhibitors and beta blockers in mild-moderate HF 1 year mortality (%) 2 1 5.7 SOLVD-T 1991 12.4 13.2 CIBIS 2 1999 8.8 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 Diuretic/ digoxin Diuretic/ digoxin Diuretic/ digoxin Diuretic/ digoxin Beta-blocker Trials comparing an aldosterone/mr antagonist to placebo (added to an ACE inhibitor) in systolic HF Aldosterone Receptor Antagonists (ARAs or MRAs): ACCF/AHA Guidelines Probability of survival 1..9.8.7.6 RALES 1663 NYHA class III/IV patients 95% ACE I/1% β blocker Spironolactone.5 RRR (95% CI) 3 (18 4)% P <.1. 1 2 3 Years from randomization Probability of survival 1..9.8.7.6 EMPHASIS HF 2737 NYHA class II patients 93% ACE I or ARB/87% β blocker Eplerenone.5 RRR (95% CI) 22 (5 36)% P =.139. 1 2 3 Years from randomization Aldosterone receptor antagonists (or MRAs) are recommended in patients with NYHA class II IV and who have LVEF of 35% or less, unless contraindicated, to reduce morbidity and mortality. Strength of Evidence = A Aldosterone receptor antagonists are recommended to reduce morbidity and mortality after an acute MI in patients who have LVEF of 4% or less who develop symptoms of HF or who have a history of diabetes mellitus, unless contraindicated. Strength of Evidence = B Pitt B, et al. N Engl J Med. 1999;341:79 717. Zannad F, et al. N Engl J Med. 21;364:11 21. Circulation 213;128:e24 327. Aldosterone Antagonists: Doses MRAs: Contraindications Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Spironolactone Aldactone 12.5-25 mg qd 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:e24-327. 4
A-HeFT All-Cause Mortality (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 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 Taylor AL. N Engl J Med 24;351:249-57. Reprinted with permission from Massachusetts Medical Society. Circulation 213;128:e24-327. ICD Therapy in HF: MADIT-II and SCD-HeFT Cumulative benefit of poly-pharmacy (and CRT) in severe HF 35 RALES 1999 1 year mortality (%) 3 25 2 1 27.3 21 COPERNICUS 21 19.7 12.8 12.6 CARE-HF 25 9.7 5 Moss et al, New Engl J Med 22 Bardy et al, New Engl J Med 25 Aldo. antag. Aldo. antag. Aldo. antag Beta-blocker Aldo. antag Beta-blocker Aldo. antag Beta-blocker CRT Evidence-Based Approaches to the Management of Heart Failure: Reducing Hospitalization and Improving Patient Outcomes Gregg C. Fonarow, MD, FAHA, FACC, FHFSA Eliot Corday Professor of Cardiovascular Medicine and Science Director, Ahmanson-UCLA Cardiomyopathy Center Co-Chief, UCLA Division of Cardiology Co-Director, UCLA Preventative Cardiology Program David Geffen School of Medicine at UCLA Los Angeles, California Sinus node inhibition with Ivabradine MOA: Blocks the hyperpolarization-activated cyclic nucleotidegated (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 5
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 SHIFT Study Results Number of Events Outcome Ivabradine HR (95% CI) ARR CV Death or HF Hospitalization 793 987.82 (.75,.9) 4.2% CV Death 449 491.91 (.8, 1.3) 1.1% HF Hospitalization 514 672.74 (.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) 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 Would Dual Blockade of the RAS with Evidenced- Based Background Therapy be Superior to Singleagent RAS Inhibition? Primary outcome: CV death or heart failure hospitalization + 5-1mg bid Aliskirenmg qd Open-label run-in 4-12 weeks Prior ACEi use discontinued Randomization 5-1mg bid (n=2336) Aliskiren 3mg qd (n=234) 5-1mg bid + Aliskiren3mg qd (n=234) Double-blind Median follow-up = 36.6 months McMurray et al. NEJM 216 6
Direct Renin Inhibition and ACE Inhibition Similar DUAL Inhibition NO BETTER and Produced More Side Effects PARADIGM-HF: Study Design Combo Ali Ena Hypotension 13.8% 1.6% 11.% Renal 4.1% 2.7% 2.7% Impairment Hyperkalemia 17.1% 1.9% 12.5% Randomization (N = 8442 patients) 1 mg bid Single-blind run-in period 1 mg bid 2 mg bid 2 mg bid Primary outcome: CV death or heart failure hospitalization Testing tolerability to target doses of enalapril and 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) McMurray et al. NEJM 216 McMurray et al. NEJM 214 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) 4 32 24 16 8 Patients at Risk 4187 4212 (n=4212) (n=4187) HR =.8 (.73-.87) P =.4 Number needed to treat = 21 18 36 54 72 9 18 126 Days After Randomization 3922 3883 3663 3579 318 2922 2257 2123 44 1488 896 853 249 236 1117 914 PARADIGM-HF: Cardiovascular Death Kaplan-Meier Estimate of Cumulative Rates (%) 32 24 16 8 HR =.8 (.71-.89) P =.8 Number need to treat = 32 (n=4212) (n=4187) 18 36 54 72 9 18 126 Days After Randomization Patients at Risk 4187 456 3891 3282 2478 1716 28 4212 451 386 3231 241 1726 994 279 693 558 PARADIGM-HF: All-Cause Mortality PARADIGM-HF: Adverse Events Kaplan-Meier Estimate of Cumulative Rates (%) 32 24 16 8 HR =.84 (.76-.93) P<.1 (n=4212) (n=4187) 18 36 54 72 9 18 126 Days After Randomization Patients at Risk 4187 456 3891 3282 2478 1716 28 4212 451 386 3231 241 1726 994 279 835 711 (n=4187) Prospectively identified adverse events (n=4212) P Value Symptomatic hypotension 588 388 <.1 Serum potassium > 6. mmol/l 181 236.7 Serum creatinine > 2.5 mg/dl 139 188.7 Cough 474 61 <.1 Discontinuation for adverse event 449 516.2 Discontinuation for hypotension 36 29 NS Discontinuation for hyperkalemia 11 NS Discontinuation for renal impairment 29 59.1 Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise ---- 7
Early Benefit of PARADIGM-HF: Mode of Death All causes CV causes Sudden Worsening HF..5.1. 1 2 4 6 8 1 12 Months after Randomization Packer et al. Circulation 214 Number 9 8 7 6 5 4 3 2 1 HR p= 835 711.84 <.1 693 558.8.4.8 311 25.8.8 184 147.79.34 Desai et al. Eur Heart J. 2 PARADIGM-HF: Hospitalization for HF (%) 18 12 9 6 3 Proportion of patients HR.79 (.71,.89) p <.1 Patients hospitalized 12 1 8 6 4 2 Number of admissions RR.77 (.67,.89) p =.4 Hospitalizations Packer et al. Circulation 214 Sacubitril/Valsartan was Effective Across a Spectrum of Risk: The MAGGIC Risk Score RATE PER1 PATIENT YEARS 25 2 1 5 CV death or HF hospitalisation 1 2 3 4 5 QUINTILE OF RISK SCORE Simpson et al. JACC 2 LCZ was effective across the spectrum of Ejection Fraction PARADIGM Enrolled > 2 patients with EF between 35-4%! PARADIGM-HF: Baseline mineralocorticoid receptor antagonist use Cardiovascular death HR.8 (.71,.89); p <.1 HR.75 (.63,.89)* HR.84 (.73,.98)* (%) Patients on an MRA and were ~4% more likely to develop SEVERE hyperkalemia than those on MRA and sacubitril/valsartan Solomon et al. Circulation HF 216 MRA - No MRA - Yes *Interaction p =.32 NEJM 214, ACC 216, AHA 216 8
Effect of Sacubitril/Valsartan in the Most Stable Patients Influence of Sacubitril/Valsartan on 3- Day Readmission 2% of the most stable patients had a primary event and 17% died In the most stable patients with a primary event, death occurred prior to a heart failure hospitalization in 51%, and 6% of these deaths were sudden Solomon et al. JACC-HF 216 Desai et al. JACC 216 Estimated Long-Term Benefit of HF Free Survival with Sacubitril/Valsartan Potential Mortality Reduction with Optimal Implementation of ARNI Claggett et al. NEJM 2 Fonarow et al. JAMA Cardiol 216 Natriuretic Peptides: NT-proBNP and BNP Mechanism: NT-proBNP and BNP Cardiomyocyte Blood Mair et al. Clin Chem Lab Med 21 NT-proBNP 14 13 12 11 1 9 8 7 6 5 4 3 2 NT-proBNP remains an accurate measure of 1 severity of HF in the setting of treatment with but BNP 2 will not 4be reliable! 6 8 Pre Run-in Baseline NT-proBNP BNP Months 5 45 4 35 3 25 2 1 5 BNP McMurray et al. NEJM 214 9
216 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for HF 216 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for HF 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 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 (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) Yancy et al. JACC 216 Yancy et al. JACC 216 Sacubitril/Valsartan Dosing HFpEF accounts for up to Half of HF Doses: 24/26 mg, 49/51 mg, 97/13 mg Starting doses: 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 OPTIMIZE-HF Registry, N=41,267 HFrEF HFpEF Fonarow et al. JACC 27 Similar Signs and Symptoms in Patients with HFpEF and HFrEF % 35 3 25 2 1 5 HFrEF HFpEF Outcomes Trials in HFpEF CHARM-Preserved I-PRESERVE PEP-CHF TOPCAT Edema PND Rest dyspnea S 3 Crackles JVP >6 cm Orthopnea Cardiomegaly CHARM Investigators 1
TOPCAT: 1 Outcome (CV Death, HF Hosp, or Resuscitated Cardiac Arrest) TOPCAT: Heart Failure Hospitalizations 351/1723 (2.4%) Total HF Hosp: Spiro 394, 475; P<.1 Spironolactone HR =.89 (.77 1.4) p=.138 32/1722 (18.6%) 245/1723 (14.2%) 26/1722 (12.%) Spironolactone HR =.83 (.69.99) p=.42 Pitt et al. NEJM 214 Exploratory: vs. Spiro by Region 216 ESC Guideline Update US, Canada, Argentina, Brazil HR=.82 (.69-.98) Interaction p=.122 Russia, Rep Georgia HR=1.1 (.79-1.51) : 28/881 (31.8%) : 71/842 (8.4%) No treatment has yet been shown 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 ischemia is also considered to be important Ponikowski et al. Eur Heart J 216 PARAMOUNT: Significant Reduction in NTproBNP with at 12 Weeks 1 862 (733,112) 835 (71, 981) NT-proBNP (pg/ml) 9 8 7 6 5 4 3 2 p =.63 783 (67,914) 5 1 Weeks Post Randomization 12 Valsartan /Valsartan:.77 (.64,.92) P =.5 65 (512, 714) Solomon et al. Lancet 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) www.clinicaltrials.gov: NCT192711 11
Summary Heart failure remains extremely morbid and deadly Current treatment of HFrEF is both empiric (diuretics, lifestyle) and evidenced-based (ACEIs, 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) 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 12