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Innovation in Clinical Care in Heart Failure Teaching slides developed based on Heart Failure Summit held on October 30-31, 2015, Barcelona, Spain Guidance for the use of the slide curriculum This educational activity is intended for an international audience of healthcare professionals, including cardiologists, primary care physicians, and other healthcare professionals involved in the management of patients with heart failure. The goal of this activity is to review the current developments, as well as the unmet needs and areas for improvement, in clinical care in heart failure. Upon completion of this activity, participants will be able to: • Recognize the burden of heart failure and understand its reasons • Understand the difficulties in preventing, diagnosing and treating patients with heart failure • Understand the need to improve a multidisciplinary approach when dealing with heart failure patients • Describe the role of new generation therapies that interrupt the vicious pathophysiology cycle leading to worsening of heart failure Educational objectives • • • • • • Increase awareness for heart failure as a disease Learn about the latest scientific and clinical advances in heart failure and adopt a guidelines adherence attitude Address unmet needs that deserve to be investigated in future clinical research Discuss the roles of different stake holders, such as payers, patient organizations, specialized nurses, primary care, cardiologists and policy makers in heart failure care Establish a multidisciplinary approach for the management of heart failure Provide practical guidance to different stakeholders involved in heart failure management Contents • HEART FAILURE: Scope of the problem • EPIDEMIOLOGY of HF • DIAGNOSIS of HF • MANAGEMENT of HF • Guidelines • Challenges • Implementation of policy and guidelines • Improving Heart Failure Management • NOVEL INSIGHTS AND INNOVATIONS IN TARGETING THE NEUROHUMORAL SYSTEM • SELF ASSESSMENT HEART FAILURE: Scope of the problem The burden of heart failure NUMBER of PATIENTS 21 MILLION adults worldwide are living with heart failure This number is expected to rise.1,2 ECONOMIC BURDEN In 2012, the overall worldwide cost of heart failure was nearly $108 BILLION.6 MORTALITY 50% of heart failure patients die within 5 years from diagnosis.5 REHOSPITALISATION Heart failure is the NUMBER 1 cause of hospitalisation for patients aged >65 years.4 COMORBIDITIES: The vast majority of HF patients has 3 or more comorbidities 3 1. Mozaffarian D et al. Circulation. 2015;131(4):e29-e322. 2. Mosterd A et al. Heart. 2007;93(9):1137-1146. 3. http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Chronic-Conditions/Downloads/2012Chartbook.pdf 4. Cowie MR et al. Oxford PharmaGenesis; 2014. http://www.oxfordhealthpolicyforum.org/AHFreport. Accessed February 18, 2015. 5. Fauci AS et al. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 6. Cook C et al. Int J Cardiol. 2014;171(3):368-376. Definition of Heart Failure Heart failure can be defined as an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues, despite normal filling pressures (or only at the expense of increased filling pressures).1 TERMINOLOGY used to describe HF2 Related to EF*: Related to time-course: Related to progression: Related to location: HFrEF (reduced ejection fraction: EF<40%) HFmEF (mildly impaired EF: EF 40-49% HFpEF (preserved ejection fraction: EF ≥50%)* New onset, transient, chronic Acute, stable, worsening Left heart, right heart, combined * There is no consensus concerning the cut-off for preserved EF2 1. McMurray et al. Eur Heart J 2012;33:1787–847 2. Dickstein K et al. Eur Heart J 2008;29:2388–442 Aetiology of HF VALVULAR HEART DISEASE • • • • Mitral Aortic Trisuspid Pulmonary MYOCARDIAL DISEASE • • • Coronary artery disease Hypertension Cardiomyopathy ENDOCARDIAL DISEASE • With/without hypereosinophilia • Endocardial fibroelastosis PERICARDIAL DISEASE • • Constrictive pericarditis Pericardial effusion HIGH OUTPUT STATES • • • • • HEART FAILURE Anaemia Sepsis Thyrotoxicosis Paget‘s disease Arteriovenous fistula Renal failure Iatrogenic (e.g. postoperative fluid infusion • • • • • Tachyarrhythmia Atrial Ventricular Bradyarrhythmia Sinus node dysfunction CONDUCTION DISORDERS VOLUME OVERLOAD • • ARRHYTHMIA • CONGENITAL HEART DISEASE Atrioventricular block McMurray et al. Eur Heart J 2012;33:1787–847 Pathophysiology of HF Injury to myocytes due to myocardial infarction or other cause ELECTRICAL INSTABILITY VENTRICULAR REMODELING REDUCTION of EF NEUROHUMORAL IMBALANCE An imbalance occurs in three key neurohumoral systems: • The renin–angiotensin–aldosterone system • The sympathetic nervous system • The natriuretic peptide system The systemic responses in the renin–angiotensin–aldosterone and sympathetic nervous systems cause further myocardial injury, and have detrimental effects on the blood vessels, and various organs, thereby creating a pathophysiological ‘vicious cycle’. The natriuretic peptide system has a protective function, which can counterbalance these detrimental effects. 1. McMurray JJ. N Engl J Med 2010;362:228–238 2. Shah AM. Lancet 2011;378:704–712 Symptoms and signs of HF The diagnosis of HF can be difficult, especially in the early stages Symptoms Signs Typical More specific Breathlessness Elevated jugular venous pressure Orthopnoea Hepatojugular reflux Paroxysmal nocturnal dyspnoea Third heart sound (gallop rhythm) Reduced exercise tolerance Laterally displaced apical impulse Fatigue, tiredness, increased time Cardiac murmur to recover after exercise Ankle swelling McMurray et al. Eur Heart J 2012;33:1787–847 McMurray et al. Eur Heart J 2012;33:1787–847 Classification of Heart Failure ACC/AHA stages of HF NYHA functional classification (based on structure and damage to heart) (based on symptoms or physical activity) Stage A At high risk for HF, but without structural or functional abnormality No signs or symptoms Stage B Developed structural heart disease strongly Class II associated with development of HF, but without signs or symptoms Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in HF symptoms Stage C Symptomatic HF associated with underlying Class III structural heart disease Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity results in HF symptoms Stage D Advanced structural heart disease and marked symptoms of HF at rest, despite maximal medical therapy Symptoms of HF present at rest. If any physical activity is undertaken, discomfort is increased Dickstein et al. Eur Heart J 2008;29:2388–442 Hunt et al. J Am Coll Cardiol 2009;53:e1–90 Class I Class IV No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnoea Natural history of HF HF is a silently progressing disease We begin to look at the disorder at the end of its natural history - that is too late! The cardiovascular continuum Vascular Remodeling environmental determinants LVH physical activity ↓ CVD risk factors & biomarkers genetic determinants Myocardial Remodeling Krum, Gilbert. Lancet 2003;362:147–58 McMurray et al. Eur Heart J 2012;33:1787–847 B Diastolic Heart Failure Systolic Dysfunction Systolic Heart Failure Disturbed Microcirculation CAD / Infarktion Stage A Diastolic Dysfunction C/D The classic domains of HFrEF are also present in HFpEF1 severely reduced exercise capacity, neuroendocrine activation, impaired quality of life Domains HFpEF HFrEF Controls Peak VO2 14.2±0.5* 13.1±0.5* 19.9±0.7 Angiotensin 9.1±0.3* 8.7±0.3* 11.5±0.4 Norepinephrine 306±64* 287±62* MLHFQ 24.8±4.4 43.8±3.9 169±80 - *P<0.05 vs controls HFpEF: HF despite absence of pump failure Half of patients with HF have HFpEF2 1. Borlaug BA and Paulus WJ. Eur Heart J 2011;32: 670–679 2. Kitzman DW et al. JAMA 2002; ;288(17):2144-2150 HFpEF is a major public health problem 40 30 20 10 0 5.5 Campbell J Am Coll Cardiol 2012 HFpEF hypertension 5.3 diabetes 4.6 hypertension 50 hypertension 60 hypertension Per 1000 patient years 70 hypertension, very elderly 80 stable angina & hypertension HF HOSPITALIZATION 69 43 7.1 7.5 11 11.5 73 Outcomes of patients with HFpEF as compared with those in trials of other cardiovascular disease, with similar ages, sex and comorbidities profiles HFpEF is a major public health problem Per 1000 patient years 50 40 30 20 11.4 15.7 0 Campbell J Am Coll Cardiol 2012 16.4 Hypertension very elderly HFpEF 76 47.2 25.6 10 hypertension hypertension hypertension 60 stable angina & hypertension 70 hypertension 80 diabetes OVERALL MORTALITY 17.3 28.7 53 54 Outcomes of patients with HFpEF as compared with those in trials of other cardiovascular disease, with similar ages, sex and comorbidities profiles HF has a detrimental effect on Quality of Life Patients with HF commonly report psychological distress, including: • depression • hostility and anxiety • limitation in their activities of daily living • disruption of work roles and social interaction with friends and family HF=heart failure; • reduced sexual activity and satisfaction Grady. Crit Care Nurs Clin North Am 1993;5:661–70 2010 Health related QoL is similar for patients with HFpEF and HFrEF 16 HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) 14 Percent distribution 12 10 8 6 4 2 0 0–<10 10 –<20 20 –<30 30 –<40 40 –<50 50 –<60 60 –<70 70 –<80 80 –<90 Better QoL MLHF summary score range 1. Lewis et al. Eur J Heart Fail 2007;9:83–91 2. Kitzman et al. JAMA 2002;288:2144-50 >90 Worse QoL • Distribution of the MLHF questionnaire responses in patients (n=2709) with HFpEF and HFrEF. Scores range from 0 to 105 with a low score reflecting a better healthrelated QoL • Distribution of MLHF QoL scores reflects the wide range of healthrelated QoL among patients with chronic HF1 • Patients with HFpEF and those with HFrEF have a similar distribution of MLHF QoL scores • Patients with HFpEF may have greatly reduced general and symptom-specific QoL2 Comorbidities in HF Comorbidities impact prognosis in patients with HF1,2 Why comorbidities are relevant in HF1: COPD Gout Hyperlipidaemia Iron deficiency Comorbidities in patients with HF Hypertension Angina Renal dysfunction 1. McMurray et al. Eur Heart J 2012;33:1787–847 2. Ennezat et al. Nephrol Dial Transplant 2011;26:3908-13 Depression Sleep disturbance Cancer Diabetes mellitus Anaemia Cachexia Obesity • Comorbidities may affect the use of treatments for HF • Drugs used to treat comorbidities may cause worsening of HF • Drugs used to treat HF and comorbidities may interact and reduce patient adherence • Most comorbidities are associated with worse clinical status and are predictors of poor prognosis in HF HF imposes a significant burden on the caregiver Caregiving tasks related to feelings of burden include personal care, such as assisting with washing and bathing and mobility1 Caregiving burden in partners of patients with HF is similar to that in partners of patients with cancer1 HF caregivers report being socially isolated, physically exhausted and unprepared for the stress of the caregiver role, with sleep and anxiety issues over current and future needs, and worry over financial concerns2 Older caregivers experience decreased psychological functioning, increased risk of health problems and mortality3 1. Luttik et al. Eur J Heart Fail 2007;9:695–701 2. Saunders. West J Nurs Res 2008;30:943–59 3. Schulz & Beach. JAMA 1999;282:2215–19 Section Summary Heart failure: Scope of the problem • Heart failure can be defined as ‘an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues, despite normal filling pressures (or only at the expense of increased filling pressures)‘ • The global burden of HF is increasing in number and complexity, due to an aging patient population, often with multiple comorbidities. Reducing readmissions can limit the burden for healthcare systems. • There are many causes of HF that result in ventricular remodeling, reduction of the left ventricular ejection fraction, and neurohumoral imbalance. • Many of the symptoms of HF are non-specific. HF severity can be classified based on structure and damage to heart (ACC/AHA) or based on symptoms or physical activity (NYHA). HF is a silently progressive condition. • HFrEF and HFpEF may present similarly within the clinical syndrome of HF. Half of patients have HFpEF. Outcomes in HFpEF patients are worse than in similar patient populations with other cardiovascular disease • HF has a large impact on quality of life, including physical activities and psychological distress. Comorbidities impact prognosis in patients with HF. • HF places a significant physical and emotional burden on the caregiver. DIAGNOSIS of HEART FAILURE Principles of diagnosis of HF All diagnostic steps are equally important Consider: Medical history, signs, symptoms Confirm: Natriuretic peptides, Echocardiography Assess clinical phenotype: HFrEF vs. HFpEF Assess etiology: Angiography, cMRI, Biopsy Risk stratification Workup for targeted therapies Presented by BM Pieske during HF SUMMIT 2015 The diagnosis of HF is a staged process A Risk assessment at preclinical stage Initial diagnostic workup in symptomatic patients • • • • Clinical assessment/Comorbidities Biomarkers (Cardiac +EOD) Echocardiography Stress test B Detailed workup in case of uncertainity • Stress echocardiography • Invasive tests & hemodynamics • Cardiac MRI • Comorbidities C Underlying pathophysiology & aetiology • • • • Presented by BM Pieske during HF SUMMIT 2015 Cardiac MRI +++ Biopsy Scintigraphy SPECT, Molecular imaging(?) Diagnosing HF The diagnosis of HFpEF is more difficult than the diagnosis of HFrEF The diagnosis of HFrEF requires three conditions to be satisfied 1. Symptoms typical of HF 2. Signs typical of HF 3. Reduced LVEF The diagnosis of HFpEF requires four conditions to be satisfied 1. Symptoms typical of HF 2. Signs typical of HF 3. Normal or only mildly reduced LVEF and LV not dilated 4. Relevant structural heart disease (LV hypertrophy/LA enlargement) and/or diastolic dysfunction McMurray et al. Eur Heart J 2012;33:1787–847 ESC HF diagnostic algorithm 2012 Acute onset Non-acute onset ECG, Possibly chest x-ray ECG, Chest x-ray Echocardiography BNP/NT-pro BNP* BNP/NT-pro BNP Echocardiography ECG normal and NT-proBNP < 300pg/mL or BNP < 100 pg/mL ECG abnormal or NT-proBNP > 300pg/mLb or BNP > 100 pg/mL b ECG abnormal or NT-proBNP > 125 pg/mLa or BNP > 35 pg/mL a ECG normal and NT-proBNP < 125pg/mL or BNP < 35 pg/mL HF unlikely c HF unlikely c Echocardiography If heart failure is confirmed by echocardiography, determine aetiology and start appropriate treatment. *In the acute setting, MR-proANP may also be used (cut-off point 120 pmol/L, i.e. <120 pmol/L = heart failure unlikely). a. Exclusion cut-off points for natriuretic peptides are chosen to minimize the false-negative rate while reducing unnecessary referrals for echocardiography. b. Other causes of elevated natriuretic peptide levels in the acute setting are an acute coronary syndrome, atrial or ventricular arrhythmias, pulmonary embolism, and severe chronic obstructive pulmonary disease with elevated right heart pressures, renal failure, and sepsis. Other causes of an elevated natriuretic level in the non-acute setting are: old age (>75 years), atrial arrhythmias, left ventricular hypertrophy, chronic obstructive pulmonary disease, and chronic kidney disease. c. Treatment may reduce natriuretic peptide concentration, and natriuretic peptide concentrations may not be markedly elevated in patients with HF-PEF. McMurray et al. Eur Heart J 2012;33:1787–847 HFA/ESC diagnostic recommendations HFpEF Symptoms or signs of HF Normal or mildly reduced LV systolic function (LVEF >50% and LVEDVI <97 mL/m2) Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness Invasive hemodynamic measurements mPCW >12 mmHg or LVEDP >16 mmHg or >48 ms or b >0.27 TD EIE′ >15 15 >EIE′ >8 Biomarkers NT-proBNP >220 pg/mL or BNP >200 pg/mL HFpEF Paulus et al. Eur Heart J 2007;28:2539–50 Biomarkers NT-proBNP >220 pg/mL or BNP >200 pg/mL Echo – blood flow Doppler EIA>50 yr <0.5 and DT>50 yr >280 ms or Ard–Ad >30 ms or LAVI >40 mL/m2 or LVMI >122 g/m2(♀); >149 g/m2 (♂) or atrial fibrillation TD EIE′ >8 Particular relevance of BNP • • • • • diagnosis staging risk stratification monitor/titrate therapy admission/discharge decisions: > rule out symptomatic LV dysfunction A normal natriuretic peptide level in an untreated patient virtually excludes significant cardiac disease Consider different cut-off values in various clinical situations Presented by K Dickstein during HF SUMMIT 2015 Section Summary Diagnosis of HF • Adequate diagnosis of HF includes screening for cardiac dysfunction in patients at risk, confirming the clinical suspicion with objective diagnostic measures, and identifying the underlying phenotype and aetiology. • The HF diagnosis should be considered at all levels of care, to guide management decisions. • The diagnosis of HFpEF is more difficult than the diagnosis of HFrEF because it is largely one of exclusion. • Measuring natriuretic peptide levels can help diagnosis. A normal natriuretic peptide level in an untreated patient virtually excludes significant cardiac disease, making an echocardiogram unnecessary. EPIDEMIOLOGY of HEART FAILURE HF is increasing in prevalence Hospital discharges for HF by gender (USA: 1979-2006)* 700 Male Discharges in thousands 600 Female 500 400 300 200 100 0 79 80 85 *Hospital discharges include people discharged alive, dead and of unknown status Lloyd-Jones et al. Circulation 2010;121:e46–e215 90 Years 95 00 05 Increasing HFpEF prevalence trends • Prevalence of HFpEF among patients with a discharge diagnosis of HF increased from 38% to 54% from 1987–20011 • Increasing prevalence of HFpEF may be a consequence of growing recognition, population aging and increases in hypertension and obesity2 70 Patients with preserved ejection fraction (%) r=0.92, p<0.001 60 50 40 30 20 0 1986 1. Owan et al. N Engl J Med 2006;355:251–9 2. Blanche et al. Swiss Med Wkly 2010;140:66–72 1990 1994 1998 2002 HFpEF & HFrEF: Similar initial hospital rates In a retrospective study of 451 patients with HF in Sweden, time from diagnosis to first post-diagnosis CV- or HF-related hospitalization was not significantly different between HFpEF and HFrEF (p=0.49 and p=0.08, respectively) Time to first CV hospitalization Time to first HF hospitalization 1.00 Survival distribution function Survival distribution function 1.00 0.75 0.50 0.25 0 HFpEF (LVEF >45%) HFrEF (LVEF ≤45%) 0.75 0.50 0.25 0 0 200 400 600 Time (days) 800 Wikstrom et al. ESC 2011 Gothenburg, Sweden, 21–24 May 2011 1,000 0 200 400 600 Time (days) Wikstrom et al. ESC 2011 Gothenburg, 800 1,000 Sweden, May 21–24, 2011 HFpEF & HFrEF: Similar hospital readmission rates p=0.09 Percentage of patients 18 16.1 16 13.5 14 12 HFpEF 10 8 6 HFrEF p=0.66 4.5 4.9 4 2 0 30-day readmission for HF* 1-year readmission for HF* *Readmission rates were calculated for the 2,339 patients who survived the index admission: 1,493 with HFrEF and 846 with HFpEF 1. Bhatia et al. N Engl J Med 2006;355:260–9 2. Fonarow et al. J Am Coll Cardiol 2007;50:768–77 3. Lenzen et al. Eur Heart J 2004;25:1214–20 • In new-onset HF, rates of readmission for HF and inhospital complications do not differ substantially between HFpEF and HFrEF1 • Readmission is as likely in HFpEF as in HFrEF, following hospital discharge, with a re-hospitalization rate of 29% within 60–90 days,2 and a median time to rehospitalization of 29 days3 Mean length of hospital stay increases with each rehospitalization for HF Length of hospital stay following hospitalization for HF Mean length of stay (days) 8.5 8.0 7.5 All HF HFrEF HFpEF Acute HF Chronic HF 7.0 6.5 6.0 First Second Third Fourth Hospitalization Fifth Korves et al. Presented at the American Heart Association Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke 2010 Scientific Sessions, Washington, D.C., May 19–21, 2010 278,307 patients in the USA with ≥1 hospitalization with a HF claim were followed from first HF hospitalization for 24 months or until disenrollment or end of data availability HFpEF & HFrEF: Similarly high mortality Survival rate among patients with a discharge diagnosis of HF in the USA was slightly higher among patients with HFpEF than those with HFrEF between 1987–20011 Respective mortality rates were 29% and 32% at 1 year and 65% and 68% at 5 years HFpEF is associated with significant morbidity and mortality, despite having a slightly higher survival rate compared with HFrEF2,3 1.0 HFrEF (LVEF <50%) HFpEF (LVEF ≥50%) Survival 0.8 0.6 0.4 0.2 p=0.03 0 0 1 2 Year 1. Owan et al. N Engl J Med 2006;355:251–9 2. Blanche et al. Swiss Med Wkly 2010;140:66–72 3. Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). Eur Heart J 2012;33:1750–7 3 4 5 HFpEF survival rates are not improving Patients with HFpEF (LVEF ≥50%) 1.0 1.0 1987–1991 1992–1996 1997–2001 0.6 0.4 1987–1991 1992–1996 1997–2001 0.8 Survival 0.8 Survival Patients with HFrEF (LVEF <50%) 0.6 0.4 0.2 0.2 p=0.005 p=0.36 0 0 0 1 2 3 Year Owan et al. N Engl J Med 2006;355:251–9 4 5 0 1 2 3 Year 4 5 Section Summary Epidemiology of HF • HF is increasing in prevalence. Changes in population demographics account for these increases. • HFpEF and HFrEF have similar initial hospitalisation rates and similar rehospitalisation rates. • Mean length of hospital stay increases with each rehospitalisation for HF • HFpEF and HFrEF have similarly high mortality. While survival rates in HFpEF have not changed in recent years, survival rates in HFrEF have improved. HF Guidelines There are many treatment objectives for chronic HF Objectives of treatment for chronic HF 1. Prognosis • reduce mortality 2. Morbidity • • • • • • • • • • • 3. Prevention Dickstein et al. Eur Heart J 2008;29:2388–442 McMurray et al. Eur Heart J 2012;33:1787–847 relieve symptoms and signs improve QoL eliminate edema and fluid retention increase exercise capacity reduce fatigue and breathlessness reduce the need for hospitalization provide end of life care occurrence of myocardial damage progression of myocardial damage remodelling of the myocardium reoccurrence of symptoms and fluid accumulation • hospitalization ACC/AHA Guidelines recommend incremental addition of treatments as HF progresses Hunt et al. J Am Coll Cardiol 2009;53:e1–90 Drugs ACEIs or ARBs in appropriate patients β-blockers in appropriate patients Devices in selected patients Implantable defibrillators Development of symptoms of HF Drugs ACEIs or ARBs in appropriate patients for vascular disease or diabetes STAGE C Structural heart disease with prior or current symptoms of HF Therapy goals All measures under Stage A Structural heart disease Therapy goals Treat hypertension Encourage smoking cessation Treat lipid disorders Encourage regular exercise Discourage alcohol intake, illicit drug use Control metabolic syndrome STAGE B Structural heart disease, but without signs or symptoms or HF Therapy goals All measures under Stages A and B Dietary salt restriction Drugs for routine use Diuretics for fluid retention ACEIs β-blockers Drugs in selected patients Aldosterone antagonists ARBs Digitalis Hydralazine/nitrates Devices in selected patients Biventricular pacing Implantable defibrillators STAGE D Refractory HF requiring specialized interventions Refractory symptoms of HF at rest STAGE A At high risk for HF, but without structural heart disease or symptoms of HF Therapy goals Appropriate measures under Stages A, B, C Decision re: appropriate level of care Options Compassionate end-oflife care/hospice Extraordinary measures Heart transplant Chronic inotropes Permanent mechanical support Experimental surgery or drugs HFpEF and HFrEF respond differently to pharmacological treatment options Treatment option HFpEF HFrEF Diuretics YES YES CCBs YES NO Beta-blockers NO YES ACEIs NO YES ARBs NO YES MR antagonists NO YES Ivabradine NO YES Digoxin NO YES H-ISDN NO YES ARNIs PARAGON-HF study YES Raina A and Kanwar M. Curr Heart Fail Rep. 2014: 11(4):374-81 Tschöpe C and Lam CS. Herz 2012: 37(8):875-9 Treatment options for chronic HF ESC Guidelines 2012 Chronic symptomatic systolic HF (NYHA II-IV) – Step 1 Diuretics to relieve symptoms/signs of congestion + ACE inhibitor (or ARB if not tolerated) ADD a beta-blocker Still NYHA class II-IV? YES ADD an MR antagonist McMurray et al. Eur Heart J 2012;33:1787–847 NO No further specific treatment Continue in disease-management programme Treatment options for chronic HF ESC Guidelines 2012 Chronic symptomatic systolic HF (NYHA II-IV) – Step 2 Still NYHA class II-IV? YES NO LVEF ≤ 35% ? YES SR and HR ≥ 70 beats/min ? NO NO YES ADD ivabradine Still NYHA class II-IV and LVEF ≤ 35% ? McMurray et al. Eur Heart J 2012;33:1787–847 No further specific treatment Continue in disease-management programme Treatment options for chronic HF ESC Guidelines 2012 Chronic symptomatic systolic HF (NYHA II-IV) – Step 3 Still NYHA class II-IV and LVEF ≤35% ? YES NO QRS duration ≥120 ms? YES NO Consider CRT-P/CRT-D Consider ICD Stil NYHA class II-IV? YES McMurray et al. Eur Heart J 2012;33:1787–847 NO Consider digoxin and/or H-ISDN If end stage, consider LVAD and/or transplantation No further specific treatment Continue in disease-management programme Adding therapies is adding life 24 month mortality NUMBER of THERAPIES (vs 0 or 1 therapy) ODDS RATIO (95% confidence interval) 2 therapies 3 therapies 4 therapies 5, 6, or 7 therapies 0.63 (0.47-0.85) 0.38 (0.29-0.51) 0.30 (0.23-0.41) 0.31 (0.23-0.42) 0 0.5 1 1.5 p=0.0026 p<0.0001 p<0.0001 p<0.0001 2 This study examined the individual and incremental clinical effectiveness of guideline-recommended therapies for patients with HF and reduced LVEF. ORs for 24-month mortality associated with the number of guideline-recommended therapies received at baseline. Analysis includes all patients from the case-control population (N=4128). The number (%) of patients receiving each number of therapies at baseline was as follows: 0 or 1, 238 (5.8%); 2, 712 (17.3%); 3, 1327 (32.2%); 4, 1123 (27.2%); and 5, 6, or 7, 728 (17.6%). Fonarow GC et al. J Am Heart Assoc 2012;1:16-26 Change in Odds of 24-Month Mortality (%) Adding therapies is adding life Betablocker Betablocker + ACEI/ARB Betablocker + ACEI/AR B + ICD Betablocker + ACEI/ARB + ICD + HF education Beta-blocker + Beta-blocker + ACEI/ARB + ACEI/ARB + ICD ICD + HF + HF education education + + anticoagulation anticoagulation for AF for AF + CRT 0% -10% -20% -30% -40% -50% -39% -60% -63% -70% -80% -76% -90% -81% -83% -81% (-28% to -49%) (-54% to -71%) (-68% to -81%) (-75% to -86%) (-77% to -88%) (-72% to -87%) P<0.0001 P<0.0001 P<0.0001 P=0.0038 P=0.1388 P=0.1208 Fonarow GC et al. J Am Heart Assoc 2012;1:16-26 Treatment options for HFpEF Improving signs & symptoms Diuretics CCBs To control sodium and water retention To relieve breathlessness and oedema To improve exercise capacity To control ventricular rate in AF To treat hypertension and myocardial ischaemia Management of underlying disease McMurray et al. Eur Heart J 2012;33:1787–847 HEART FAILURE SUMMIT 2016, BARCELONA Adequate treatment of hypertension Adequate treatment of myocardial ischaemia Treatment options for HFpEF Improving prognosis ‘No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFpEF.’ (ESC Guidelines 2012) STUDY CHARMPreserved PEP-CHF I-Preserve Study drug Candesartan Perindopril Irbesartan McMurray et al. Eur Heart J 2012;33:1787–847 Yusuf S et al. Lancet 2003;362:777 Cleland JG et al. Eur Heart J 2006;27:2338 Massie BM et al. NEJM 2008;359:2456 # Endpoint Patients 3023 850 4128 Outcome Yusuf S et al Lancet 2003 CV death or HF hospitalization Death or HF hospitalization Death or HF hospitalization Publication Primary end-point not met Cleland JG et al Eur Heart J 2006 Massie BN et al NEJM 2008 Holistic management of HF ESC Guidelines 2012 Management programmes for patients with HFrEF & HFpEF Characteristics • • • Should employ a multidisciplinary approach Should target high-risk symptomatic patients Should include competent and professionally educated staff Components • • • • • • • • • Optimized medical and device management Adequate patient education, with special emphasis on adherence and self-care Patient involvement in symptom monitoring and flexible diuretic use Follow-up after discharge Increased access to healthcare Facilitated access to care during episodes of decompensation Assessment of (and appropriate intervention in response to) an unexplained increase in weight, nutritional status, functional status, quality of life, and laboratory findings Access to advanced treatment options Provision of psychosocial support to patients and family and/or caregivers McMurray et al. Eur Heart J 2012;33:1787–847 McMurray et al. Eur Heart J 2012;33:1787–847 ESC recommendations for exercise prescription and multidisciplinary management RECOMMENDATIONS CLASS LEVEL It is recommended that regular aerobic exercise is encouraged in patients with heart failure to improve functional capacity and symptoms I A It is recommended that patients with heart failure are enrolled in a multidisciplinary care management programme to reduce the risk of heart failure hospitalization I McMurray et al. Eur Heart J 2012;33:1787–847 A • Services, such as cardiac rehabilitation and palliative care, must be integrated into the overall provision for patients with HF • Multidisciplinary management programmes are vital, designed to improve outcomes through structured follow-up with patient education, optimization of medical treatment, psychosocial support, and improved access to care. Personalised medicine in HF Personalisation for patients with HF will surely improve in the future, but also today one does not fit all Personalisation by traditional biomarkers: • • • • Echo ECG Blood Pressure Laboratory examinations (renal function, electrolytes, hemoglobin, glycemia) Other more recent biomarkers How can we improve the personalisation of treatment in the future • • • Genetics Pharmacogenomics Gene therapy Presented by A. Maggioni during HF SUMMIT 2015 Section Summary Summary: HF Guidelines • ACE-inhibitors, beta-blockers and mineralocorticoid receptor antagonists form the cornerstone of HF therapy, given their mortality benefit. Incremental addition of treatments is recommended as HF progresses: Adding therapies is adding life. • HFrEF and HFpEF differently respond to treatment. Treatment in HFpEF is aimed to improve signs and symptoms, as no treatment has yet been shown to improve prognosis in HFpEF. • HF care is already somewhat personalised, since management is guided by traditional biomarkers (echo, ECG, blood pressure, laboratory examinations). In the future, genetics, pharmacogenomics and gene therapy may yield more targeted treatment strategies. • The ESC guidelines also recommend regular aerobic exercise and enrolment in care-management programmes. MANAGEMENT of HEART FAILURE Challenges Adherence to guidelines Euro Heart Survey on Heart Failure Diuretics • The most commonly prescribed class of agent ACE inhibitors • • • Betablockers Komajda M et. Eur Heart J 2003;24:464–474 Used in 61% of patients and almost 80% of those with HFrEF Reached 50-60% of the target recommended dose Captopril was prescribed at much lower doses • Less widely used (overall 37%, in patients with HFrEF 49%) • Daily dosage far below the target dose used in randomized trials Adherence to guidelines Predictor of outcome in chronic heart failure: the MAHLER survey 6 month hospitalisation rate (%) 20.6 P = 0.0003 P = 0.0003 15.9 14.7 11.2 9.7 6.7 Good Moderate Adherence Low CHF HOSPITALISATION Komajda. Eur. Heart J 2005 Aug;26(16):1653-9. Good Moderate Adherence Low CV HOSPITALISATION Hyperkalemia impacts ACEI treatment Results from BIOSTAT • • • • Prospective, observational, multicenter study in Europe N = 2,517 New-onset or worsening heart failure, with or without hospitalisation Not previously treated with ACEi/ARBs or receiving ≤50% of target dose at time of inclusion Subjects at target dose (%) 30 25 <3.6 mmol/L 20 3.6 - 5.0 mmol/L >5.0 mmol/L 15 10 5 P=0.026 0 Baseline 3 months9 months Time Presented by P. van der Meer during HF SUMMIT 2015 Improving symptoms, EC, and QoL in HF Relevant co-morbidities in CHF that require medical attention Targeting some of the comorbidities will improve symptoms - CAD / ischemia & Hypertension & Atrial Fibrillation - Diabetes mellitus & Metabolic syndrome - Sleep apnoea - Depression / other neurological disease - Renal dysfunction and kidney injury - Anemia and iron deficiency - COPD - Liver & bowel dysfunction - Cachexia & muscle wasting Presented by S. Anker during HF SUMMIT 2015 Consider individual preferences regarding improving prognosis vs. symptoms Managing AF in patients with HF AF and HF beget each other Heart failure 30-41% 33-56% Atrial fibrillation Presented by D. Kotecha during HF SUMMIT 2015 Management of AF in HF 1. AF in HF patients usually signifies a deteriorated clinical picture associated with worse outcomes, regardless of LVEF 2. HFrEF patients in AF may not respond to usual therapies in the same way but a pragmatic approach is important 3. Currently catheter ablation of AF is indicated for symptoms only 4. Rate control using beta-blockers or digoxin has no effect on mortality (we need more data comparing quality of life and LVEF) 5. Anticoagulation to prevent thromboembolism is indicated in most patients AF is an umbrella term and individual characteristics will ultimately determine the effectiveness of therapy and prognosis Presented by D. Kotecha during HF SUMMIT 2015 Treatment options for AF in HFrEF/HFpEF Ventricular rate-control in persistent/permanent atrial fibrillation HFpEF HFrEF Beta-blocker Ventricular rate controlled yes Rate-limiting CCB (or b-blocker) Ventricular rate controlled no yes no Add digoxin Ventricular rate controlled? no yes Substitute b-blocker (or ratelimiting CCB) for digoxin Ventricular rate controlled? yes Substitute amlodarone for digoxin Ventricular rate controlled? no Seek specialist advice, including consideration of AV node ablation yes Maintenance therapy no Add digoxin Ventricular rate controlled? McMurray et al. Eur Heart J 2012;33:1787–847 yes no Seek specialist advice, including consideration of AV node ablation Section Summary Challenges in HF management • Although prescription of ACE inhibitors and beta-blockers is increasing, they still remain underused. Adherence of physicians to treatment guidelines is a strong predictor of fewer CV hospitalizations in actual practice. • Hyperkalemia may limit the use of guideline recommended therapy. Compounds are in development to reduce potassium levels. • Targeting certain comorbidities in chronic HF may improve symptoms, but the balance between improving symptoms vs. improving prognosis needs to be discussed with the individual patient. • Preventing loss of fat and skeletal muscle is important, and also preventing anaemia and iron deficiency can improve symptoms and quality of life. • Atrial fibrillation and heart failure show strong interdependence and affect each others outcome, thus management of AF is important in patients with HF. MANAGEMENT of HEART FAILURE Implementation of policy and guidelines Key areas of development in HF Effective innovations include: Implementation of Guidelines: evidenced based medicine Care delivery: HF management programmes, role of HF nurse, role of ER physicians and GPs Education: nurses, primary care, HF speciality, patients Prevention: primary, secondary prevention Surveys/Registries: ESC EORP Networking: ESC, Associations, National Societies Cyberspace: online education Presented by K Dickstein during HF SUMMIT 2015 How to benefit optimally from available interventions Evidence-based policy recommendations • have the potential to drive improvements with the power to save lives, • aim to make prevention and management of HF a global health priority, Improving HF care • involve policy-makers, healthcare professionals, professional associations, organizations that fund healthcare, industry, the public, caregivers and patients themselves HF prevention: Policy recommendations Oxford Health Policy Forum – policy iniative Promote heart failure prevention Improve heart failure awareness among healthcare professionals Ensure equity of care for all patients with heart failure Support and empower patients and their caregivers Promote heart failure research Presented by J. Riley during HF SUMMIT 2015 http://www.oxfordhealthpolicyforum.org/reports/heart-failure/heart-failure, accessed 14.12.2015 Acute HF: Policy recommendations Oxford Health Policy Forum – policy iniative Promote acute heart failure prevention Appoint experts to lead heart failure care across the disciplines Optimise care transitions Develop and implement better measures of care quality Improve end-of-life care Improve patient education and support Provide equity of care for all patients with heart failure Stimulate research into new therapies Presented by J. Riley during HF SUMMIT 2015 http://www.oxfordhealthpolicyforum.org/reports/heart-failure/heart-failure, accessed 14.12.2015 Establishing an integrated hospitalprimary care HF programme Diagnose the problem Chronic Heart Failure Inventarisation of unmet needs System Designed for Acute Conditons Presented by J. Comin-Colet during HF SUMMIT 2015 Create an answer Chronic Care Model Integrated hospital-PC HF programme Challenges In order for an integrated hospital-primary care HF programme to be successful, various types of barriers need to be overcome: SYSTEMIC BARRIERS - related to awareness among the public and policy makers INSTITUTIONAL BARRIERS - related to facilitation of truly integrated healthcare pathways PROFESSIONAL BARRIERS - to stimulate teamwork and shared leadership. Presented by J. Comin-Colet during HF SUMMIT 2015 Systemic barriers 1. Increase the awareness of heart failure as a problem for patients and for the sustainability of public healthcare systems 2. Increase the awareness among healthcare services managers and healthcare professionals that multidisciplinary team management and integrated care are the best approaches for HF patients 3. From a societal perspective, place the importance of heart failure at the same level of other important chronic conditions such as cancer Presented by J. Comin-Colet during HF SUMMIT 2015 Institutional barriers 1. Promote the creation of truly integrated healthcare pathways and clinical processes for HF patients (local settings) with professional teams working at various levels of care 2. Healthcare pathways for the management of HF (functional teams) with organizational autonomy and executive capacity (support form managers and healthcare authorities) 3. Promote the access of professionals involved in the care of HF patients to quality indicators and to participate in the process of creation of multidisciplinary teams Presented by J. Comin-Colet during HF SUMMIT 2015 Professional barriers 1. Increase TEAMWORK culture among healthcare professionals 2. Allow shared leadership 3. Training, training, training (at all levels of care) 4. Health and social integration (in multidisciplinary teams but also in early stages of training and education) Presented by J. Comin-Colet during HF SUMMIT 2015 Section Summary Implementation of policy and guidelines • A broad range of important innovations to manage HF is already available. Guideline-recommended evidence-based medicine, multidisciplinary HF management programmes, prevention programmes can be really effective, provided that they are adequately applied in clinical practice. • The Oxford Health Policy evidence-based policy recommendations have the potential to drive improvements with the power to save lives, with the aim to make prevention and management of HF a global health priority. • Multidisciplinary care pathways are important to ensure continuity and equal access of care. The local situation and patient preferences should be considered when organising care. • Several barriers (systemic, institutional and professional) may be faced when setting up an integrated hospital-primary care HF programme. MANAGEMENT of HEART FAILURE Improving Heart Failure Management Perspectives from stake holders Current challenges in HF Stake holders exchanged different perspectives and shared views on how Heart Failure management can be improved: Patient Cardiologist Primary Care Physician Heart Failure Nurse A patient’s perspective Current challenges in HF Direct from the Patient Community: What would people like to see? • • • • • • • Access to care and therapies needs to be equal Better initial engagement of patients in self management Better understanding of HF from non-cardiologists Better continuity of care Are the pathways followed? Patients look at pathways as well Speed up access to help and self learning. How you are dealt with in ER – Don’t you believe me? I have HF! Presented by N Hartshorne Evans during HF SUMMIT 2015 Cardiologist’s perspective TOPIC RECOMMENDATION Improving HF management Adherence to guidelines • • Fight medical inertia Create a national quality control programme Treatment optimisation • • • Prevent the decompensation of the patient Create a nationwide system (prognostic markers) Improve early detection of HF degradation and need for LVAD Education • Integrate patient self-management education into basic HF management Prevention • Improve prevention of HF Multidisciplinary approach • Create acute HF teams in each regional hospital to streamline the acute HF management Create a real cooperation process between nurses and doctors • Optimisation of care transition • • • Limit time from admission to treatment at the emergency department by improving and speeding up the intra-hospital pathways Try to reduce in-hospital stay Bridge the time between hospital discharge and primary care physician follow-up Telemedicine • Integrate telemedicine into healthcare process Presented by P. Jourdain during HF SUMMIT 2015 Primary care physician’s perspective TOPIC RECOMMENDATION Improving HF management Adherence to guidelines • Implement use of evidence-based medications better Treatment optimisation • Better identify higher risk HF patients using natriuretic peptides Education • • • Improve understanding of HF burden for primary care Improve understanding of HF impact on patients Improve understanding of HF impact on health system costs Prevention • Get evidence on whether screening strategies work Early diagnosis • • • New treatment options • Presented by R. Hobbs during HF SUMMIT 2015 Provide open access to natriuretic peptide assays – for early diagnosis Provide open access to echocardiography – for early diagnosis Consider specialist referral after diagnostic triage – for early diagnosis Develop more treatment options HF nurse’s perspective TOPIC Improving HF management RECOMMENDATION Adherence to guidelines • • Adherence to the guidelines with regard to fluid and salt restriction More practical knowledge regarding advice on exercise Treatment optimisation • • More time for the patient Use of telemonitoring to optimise care Education • Development of a clear European HF nurse educational programme and profile, including training on the main comorbidities and challenging subjects such as motivational interviewing and end-of-life conversations Multidisciplinary approach • • • • Better integration of HF nurse specialism across primary and secondary care Nurses as consultants in primary care as well as in palliative care teams Bridge between the hospital, GP’s and HF outpatient clinic nurses More clarity on the roles and responsibilities in the team and recognition of capabilities Practical tools for the patient • • Research • • Presented by T. Jaarsma during HF SUMMIT 2015 Medication reminder systems HF medication up-titration tools Collect evidence for optimal non pharmacological heart failure care Examine patient motivation methods Different disciplines have several common needs CARDIOLOGIST Improving HF management Optimisation of care transition Telemedicine Multidisciplinary approach Prevention Adherence to guidelines Early diagnosis New treatment options PC PHYSICIAN Views expressed by care professionals during HF SUMMIT 2015 Treatment optimisation Education Practical tools for the patient Research HF NURSE Section Summary Improving HF Management The HF patient community generally feels well looked after, with specific appreciation of HF nurses. Patients do feel that continuity of care could be improved as well as awareness among noncardiologists, including the understanding of the mental impact of the syndrome Based on the experience of a cardiologist, a primary care physician and an HF nurse, HF care could be improved by: • Optimising care pathways, from earlier initiation of therapy already in the emergency room, to facilitating the transition from hospital to patient home. Open access to natriuretic peptide assays and ECG can improve diagnosis in primary care and referral pathways • Improving education about the syndrome and awareness of disease impact at all levels: among patients, primary care physicians, nurses and specialists • True cooperation between nurses and doctors, with a clear division of roles and responsibilities • Better implementation of evidence-based guideline recommendations • Educating patients on self-management, taking into account individual preferences and capabilities Novel insights and innovations in targeting the neurohumoral system An imbalance occurs in three key neurohumoral systems β-blockers SNS Epinephrine Norepinephrine Natriuretic peptide system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy HFrEF SYMPTOMS & PROGRESSION α1, β1, β2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility RAAS inhibitors (ACEI, ARB, MRA) RAAS Ang II AT1R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs 1 Benefits of β-blockers indicate that the SNS also plays a key role1 1. McMurray for et al. Eurabbreviation Heart J 2012;33:1787–847 See notes Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42 Kemp & Conte. definitions Cardiovascular Pathology 2012;365–71 Schrier & Abraham. N Engl J Med 1999;341:577–85 Landmark trials in patients with HFrEF SOLVD-T1 (1991) 2,569 patients Key benefits of enalapril (ACEI) vs placebo: • 16% all-cause mortality CHARM-Alternative3 (2003) 2,028 patients Key benefits of candesartan (ARB) vs placebo: • 23% CV mortality or HF hospitalization 1990s CIBIS-II2 (1999) 2,647 patients Key benefits of bisoprolol (BB) vs placebo: • 34% all-cause mortality 1. SOLVD Investigators. N Engl J Med 1991;325:293–302 2. CIBIS-II Investigators. Lancet 1999;353:9–13; 3. Granger et al. Lancet 2003;362:772−6 4. McMurray et al. Lancet 2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85 6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–1004 SHIFT5 (2010) 6,558 patients Key benefits of ivabradine (If inhibitor) vs placebo: • 18% CV death or HF hospitalization 2000s CHARM-Added4 (2003) 2,548 patients Key benefits of candesartan (ARB) vs placebo: • 15% CV mortality or HF hospitalization PARADIGM-HF7 (2014) 8,442 patients Key benefits of LCZ696 (ARNI) vs enalapril: • 20% CV mortality or HF hospitalization 2010s EMPHASIS-HF6 (2011) 2,737 patients Key benefits of eplerenone (MRA) vs placebo: • 37% CV mortality or HF hospitalization Percentages are relative risk reductions vs comparator Mortality in HFrEF remains high despite the introduction of therapies that improve survival Survival rates in chronic HF have improved with the introduction of new therapies1 Reduction in relative risk of mortality vs placebo ACEI* β-blocker* MRA* ARB* 16% 17% (4.5% ARR; mean follow up of 41.4 months) SOLVD1,2 (3.0% ARR; median follow up of 33.7 months) 30% 34% (5.5% ARR; mean follow up of 1.3 years) CIBIS-II3 (11.0% ARR; mean follow up of 24 months) RALES4 CHARMAlternative5 However, significant mortality remains – ~50% of patients die within 5 years of diagnosis6–8 *On top of standard therapy at the time of study (except in CHARM-Alternative where background ACEI therapy was excluded). Patient populations varied between trials and as such relative risk reductions cannot be directly compared. SOLVD (Studies of Left Ventricular Dysfunction), CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and RALES (Randomized Aldactone Evaluation Study) enrolled chronic HF patients with LVEF≤35%. CHARM-Alternative (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) enrolled chronic HF patients with LVEF≤40% 1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Investigators. N Engl J Med 1991;325:293–302; 3. CIBIS-II Investigators. Lancet 1999;353:9– 13; 4. Pitt et al. N Engl J Med 1999;341:709-17; 5. Granger et al. Lancet 2003;362:772–66. 6. Go et al. Circulation 2014;129:e28e292; 7. Yancy et al. Circulation 2013;128:e240–327; 8. Levy et al. N Engl J Med 2002;347:1397–402 Evolution of pharmacologic approaches in HF: LCZ696 as a new alternative to an ACEI or ARBs in patients with HFrEF1 β-blockers SNS Epinephrine Norepinephrine Neprilysin inhibitors NP system NPRs HF SYMPTOMS & PROGRESSION NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresi s Vasopressin Aldosterone Fibrosis Hypertrophy Vasoconstrictio n RAAS activity Vasopressin Heart rate Contractility RAAS inhibitors (ACEI, ARB, MRA) RAAS Ang II INACTIVE FRAGMENTS LCZ696 α1, β1, β2 receptors AT1R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis LCZ696: enhancement of natriuretic and other vasoactive peptides, with simultaneous RAAS suppression 1. McMurray et al. Eur J Heart Fail 2013;15:1062–73 Figure references: Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42 Kemp & Conte. Cardiovascular Pathology 2012;365–71 Schrier & Abraham. N Engl J Med 2009;341:577–85 LCZ696 simultaneously inhibits neprilysin (via LBQ657) and blocks AT1 receptors (via valsartan) LCZ696 ANP, BNP, CNP, other vasoactive peptides* RAAS Angiotensinogen (liver secretion) Sacubitril (AHU377; pro-drug) Inactive fragments LBQ657 (NEP inhibitor) Ang I Valsartan O O Enhancing Vasorelaxation Blood pressure Sympathetic tone Aldosterone levels Fibrosis Hypertrophy Natriuresis/diuresis Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42 Schrier & Abraham. N Engl J Med 2009;341:577–85 Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9 Feng et al. Tetrahedron Letters 2012;53:275–6 N OH N OH N HO N O AT1 receptor Inhibiting O HN O Ang II NH Vasoconstriction Blood pressure Sympathetic tone Aldosterone Fibrosis Hypertrophy PARADIGM-HF: Study design For more details on the PARADIGM-HF study, refer to the dedicated slide kit Randomization n=8442 Double-blind Treatment period Single-blind active run-in period LCZ696 200 mg BID§ Enalapril 10 mg BID* LCZ696 100 mg BID‡ LCZ696 200 mg BID§ Enalapril 10 mg BID# 2 Weeks 1–2 Weeks 2–4 Weeks Median of 27 months’ follow-up On top of standard HFrEF therapy (excluding ACEIs and ARBs) . McMurray et al. Eur J Heart Fail 2013;15:1062–73 McMurray et al. Eur J Heart Fail 2014;16:817–25 McMurray et al. N Engl J Med 2014;371:993–1004 PARADIGM-HF: Primary objective To evaluate the effect of LCZ696 200 mg BID compared with enalapril 10 mg BID, in addition to conventional HFrEF treatment, in delaying time to first occurrence of either CV death or HF hospitalization1 Rationale for endpoint selection Primary outcome of CV death or HF hospitalization was chosen as the one that best reflects the major mortality and morbidity burden of HFrEF1,2 • ~80% of deaths in recent trials in patients with HFrEF are CV related 35 • HF is associated with a high risk of hospitalization,6 representing the leading cause of hospitalization in patients aged ≥65 years69 The most commonly used primary endpoint in recent HF trials: CHARM-Added, SHIFT and EMPHASIS-HF1 1. McMurray et al. Eur J Heart Fail 2013;15:1062–73; 2. Dunlay et al. Circ Cardiovasc Qual Outcomes 2011;4:68–75; 3. McMurray et al. Lancet 2003;362:767–77; 4. Swedberg et al. Lancet 2010;376:875–88; 5. Zannad et al. N Engl J Med 2011;364:11–2; 6. Cowie et al. Oxford Health policy Forum 2014; 7.Hunt et al. J Am Coll Cardiol 2009;53:e1–90; 8.Yancy et al. Circulation 2013;128:e240–327; 9. Rodriguez-Artalejo et al. Rev Esp Cardiol 2004;57:163–70 PARADIGM-HF: Patient disposition 10,513 patients entered enalapril run-in phase (median duration, 15 days; interquartile range [IQR], 14–21) 1,102 discontinued study: 591 (5.6%) had adverse event 66 (0.6%) had abnormal laboratory or other test result 171 (1.6%) withdrew consent 138 (1.3%) had protocol deviation, administrative problem or were lost to follow-up 49 (0.5%) died 87 (0.8%) had other reasons 9,419 entered LCZ696 run-in phase (median duration, 29 days; IQR, 26–35) 977 discontinued study: 547 (5.8%) had adverse event 58 (0.6%) had abnormal laboratory or other test result 100 (1.1%) withdrew consent 146 (1.6%) had protocol deviation, had administrative problem, or were lost to follow-up 47 (0.5%) died 79 (0.8%) had other reasons 8,442 underwent randomization 43 were excluded: 6 did not undergo valid randomization 37 were from four sites prematurely closed because of major Good Clinical Practice violations 4,187 were assigned to receive LCZ696 4,176 had known final vital status 11 had unknown final vital status McMurray et al. N Engl J Med 2014;371:993–1004 4,212 were assigned to receive enalapril 4,203 had known final vital status 9 had unknown final vital status PARADIGM-HF: Summary of baseline characteristics LCZ696 (n=4,187) Enalapril (n=4,212) Age, years Women, n (%) Ischemic cardiomyopathy, n (%) LV ejection fraction, % 63.8 ± 11.5 879 (21.0) 2,506 (59.9) 29.6 ± 6.1 63.8 ± 11.3 953 (22.6) 2,530 (60.1) 29.4 ± 6.3 NYHA functional class, n (%) II III 2,998 (71.6) 969 (23.1) 2,921 (69.3) 1,049 (24.9) 122 ± 15 72 ± 12 1,631 (885–3,154) 255 (155–474) 1,451 (34.7) 121 ± 15 73 ± 12 1,594 (886–3,305) 251 (153–465) 1,456 (34.6) 3,363 (80.3) 1,223 (29.2) 3,899 (93.1) 2,271 (54.2) 623 (14.9) 292 (7.0) 3,375 (80.1) 1,316 (31.2) 3,912 (92.9) 2,400 (57.0) 620 (14.7) 282 (6.7) Characteristic* SBP, mmHg Heart rate, beats/min NT-proBNP, pg/mL (IQR) BNP, pg/mL (IQR) History of diabetes, n (%) Treatments at randomization, n (%) Diuretics Digitalis β-blockers Mineralocorticoid antagonists ICD CRT *Mean ± standard deviation, unless stated. McMurray et al. N Engl J Med 2014;371:993–1004 Primary endpoint: Death from CV causes or first hospitalization for HF 1.0 Enalapril Cumulative probability 0.6 LCZ696 Hazard ratio = 0.80 (95% CI: 0.73–0.87) p<0.001 0.4 0.2 0 0 No at risk LCZ696 Enalapril 180 360 540 720 900 1,080 Days since randomization 4,187 4,212 3,922 3,883 McMurray et al. N Engl J Med 2014;371:993–1004 3,663 3,579 3,018 2,922 2,257 2,123 1,544 1,488 896 853 249 236 1,260 Primary outcome Outcome, n % LCZ696 (n=4,187) Enalapril (n=4,212) Hazard ratio* (95% CI) p value‡ Primary composite outcome Death from CV causes or first hospitalization for worsening of HF 914 (21.8) 1,117 (26.5) 0.80 (0.73–0.87) <0.001 Death from CV causes 558 (13.3) 693 (16.5) 0.80 (0.71–0.89) <0.001 First hospitalization for worsening of HF 537 (12.8) 658 (15.6) 0.79 (0.71–0.89) <0.001 The difference in favor of LCZ696 was seen early in the trial and at each interim analysis Over the duration of the trial, the numbers of patients who would need to have been treated (NNT) to prevent: • one primary event was 21 patients, and • one death from CV causes was 32 patients *Calculated with the use of stratified cox proportional-hazard models; ‡Two-sided p-values calculated by means of a stratified log-rank test without adjustment for multiple comparisons. McMurray et al. N Engl J Med 2014;371:993–1004 Prospectively defined safety events LCZ696 (n=4,187) Enalapril (n=4,212) p value 588 (14.0) 112 (2.7) 388 (9.2) 59 (1.4) <0.001 <0.001 139 (3.3) 63 (1.5) 188 (4.5) 83 (2.0) 0.007 0.10 674 (16.1) 181 (4.3) 474 (11.3) 727 (17.3) 236 (5.6) 601 (14.3) 0.15 0.007 <0.001 10 (0.2) 5 (0.1) 0.19 Catecholamines or glucocorticoids without hospitalization 6 (0.1) 4 (0.1) 0.52 Hospitalized without airway compromise Airway compromise 3 (0.1) 0 1 (<0.1) 0 0.31 --- Event, n (%) Hypotension Symptomatic Symptomatic with SBP <90 mmHg Elevated serum creatinine ≥2.5 mg/dL ≥3.0 mg/dL Elevated serum potassium >5.5 mmol/L >6.0 mmol/L Cough Angioedema (adjudicated by a blinded expert committee) No treatment or use of antihistamines only • Fewer patients in the LCZ696 group than in the enalapril group stopped their study medication because of an AE (10.7 vs 12.3%, p=0.03) McMurray et al. N Engl J Med 2014;371:993–1004 PARADIGM-HF results - efficacy • ‘…angiotensin receptor–neprilysin inhibition with LCZ696 was superior to ACE inhibition alone in reducing the risks of death and of hospitalization for HF’ • ‘The magnitude of the beneficial effect of LCZ696, as compared with enalapril, on CV mortality was at least as large as that of long-term treatment with enalapril, as compared with placebo.’ • ‘This robust finding provides strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the RAS alone in patients with chronic HF.’ • ‘…results are applicable to a broad spectrum of patients with HF, including those who are currently taking an ACE inhibitor or ARB or who are likely to be able to take such an agent without having unacceptable side effects.’ McMurray et al. N Engl J Med 2014;371:993–1004 PARADIGM-HF Safety results • The superiority of LCZ696 over enalapril was not accompanied by important safety concerns • Fewer patients stopped their study medication because of an adverse event in the LCZ696 group than in the enalapril group • There was no increase in the rate of discontinuation due to possible hypotension-related adverse effects, despite a higher rate of symptomatic hypotension in the LCZ696 group • Fewer patients in the LCZ696 group developed renal impairment, hyperkalemia or cough than in the enalapril group • The LCZ696 group had a higher proportion of patients with non-serious angioedema, but LCZ696 was not associated with an increase in serious angioedema McMurray et al. N Engl J Med 2014;371:993–1004 Patients with HFpEF may require novel approaches to treatment HFrEF1 HFpEF1,2 • • • • • • Multiple, randomized controlled, double-blinded, clinical trials Therapeutic strategies based on outcomes General consensus on treatment among the HF community Randomized controlled trials have been supported by observational data Evidence-based medicine 1. McMurray et al. Eur Heart J 2012;33:1787–847 2. Blanche et al. Swiss Med Wkly 2010;140:66–72 • • • • Mostly mechanistic studies and small, non-definitive trials Therapeutic strategies based on symptoms and co-morbidities Limited consensus on treatment among the HF community Disconnect between randomized controlled trials and observational data Anecdote-based medicine There is a need for therapeutic advances in patients with HFpEF While recent advances in the management of HFrEF have resulted in a significant extension of life expectancy,1–5 this is not reflected in HFpEF6 No proven therapies exist for the treatment of HFpEF6 and little progress has been made towards identifying a suitable treatment in the last 30 years There are few approved treatments recommended for the management of signs and symptoms of HFpEF6* CCB‡§ (verapamil, diltiazem) Pre-1980 1985 1990 Digoxin‡ Loop diuretics (e.g. furosemide, bumetanide) 1995 2000 Beta-blocker‡ (bisoprolol) 1. Dickstein et al. Eur Heart J 2008;29:2388–442; 2. SOLVD Investigators. N Engl J Med 1991;325:293–302; 3. Granger et al. Lancet 2003;362:772–6; 4. Pitt et al. N Engl J Med 2003;348:1309–21; 5. Zannad et al. N Engl J Med 2011;364:11–21; 6. McMurray et al. Eur Heart J 2012;33:1787–847 2005 2010 2015 There are several ongoing studies of therapies in development for HFpEF NCT01354613 Dobutamine Amlodipine NCT00839228 Perhexiline PARAGON-HF LCZ696 2009 Phase II Phase III 2010 2011 NCT01516346 Isosorbide Dinitrate/ Isosorbide Dinitrate + Hydralazine Phase IV 2012 D-HART2 Anakinra ROPA-DOP Furosemide Dopamine NCT01726049 Sildenafil 2014 2013 ULTIMATEHFpEF* Udenafil SOCRATESPRESERVED Vericiguat (BAY1021189) 2015 NCT02262078 Sodium Nitrite Inhalation Solution NCT02053246 Nebivolol Recruiting studies organized according to start date of trial. *The ULTIMATE-HFpEF trial has since terminated. Information obtained from: http://clinicaltrials.gov/ct2/results?term=HFpEF&recr=Open&cond=%22H eart+Failure%22&pg=1 Last accessed Nov 27 2014 PARAGON-HF: Study design Target patient population: 4,300 patients with symptomatic HF (NYHA Class II–IV) and LVEF 45% Randomization 1:1 Double-blind treatment period Active run-in period LCZ696 200 mg BID Screening Valsartan 80 mg BID* LCZ696 100 mg BID Valsartan 160 mg BID On top of optimal background medications for comorbidities (excluding ACEIs and ARBs) up to 2 weeks 3–8 weeks ~240 weeks Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events) *Valsartan 40 mg BID (up to 2 weeks) followed by valsartan 80 mg BID as an optional starting run-in dose for those patients being treated with less than the minimum dose of ACEI or ARB at Visit 1; Solomon et al. Poster presentation at ESC-HF Congress, 25 May 2013; Novartis data on file: GMA&HEOR_LCZ696B_PARAGON-HF study_D2301_001_2.0 PARAGON-HF: Key objectives Primary objective: To compare the effect of LCZ696 with valsartan in reducing the rate of the composite endpoint of CV mortality or total (first and recurrent) HF hospitalizations Secondary objectives: To compare the effect of LCZ696 with valsartan in: • reducing the rate of the composite endpoint of CV mortality, total HF hospitalizations, total non-fatal strokes and total non-fatal MIs* • improving NYHA functional classification at 8 months • delaying time to new onset AF • delaying time to all-cause mortality *Total defined as first and all recurrent events Solomon et al. Poster presentation at ESC-HF Congress, 25 May 2013 PARAGON-HF: Key inclusion and exclusion criteria Key inclusion criteria: Key exclusion criteria: Age 55 years; LVEF 45% History of LVEF <45% Symptoms of HF requiring treatment with MI, CABG or any event within the diuretic(s) for 30 days prior to study entry Current symptomatic HF (NYHA class IIIV) 6 months prior to study entry that may have reduced LVEF (unless LVEF confirmed as 45%) Requirement for treatment with two or more Structural heart disease of the following: ACEI, ARB or renin inhibitor (LAE and/or LVH) SBP <110 mmHg OR SBP 180 mmHg at study entry* AND either Serum potassium >5.2 mmol/L at study entry eGFR <30 mL/min/1.73m2 at study entry HF hospitalization* within 9 months prior to study entry OR Elevated NTproBNP (>300 pg/mL for patients with SR or >900 pg/mL for patients with AF) *If SBP >150 mmHg and <180 mmHg, the patient should be receiving ≥3 antihypertensive drugs Solomon et al. Poster presentation at ESC-HF Congress, 25 May 2013 Section Summary Novel strategies targeting the neurohumoral system • Overactivation of the RAAS and SNS is detrimental in HFrEF and underpins the basis of therapy. • Mortality in HFrEF remains high despite the introduction of new therapies that improve survival. • The ARNI (RAAS and neprilysin inhibitor) LCZ696 simultaneously inhibits neprilysin and blocks AT1 receptors. In addition to the three cornerstone therapies of heart failure, replacing ACE inhibition by an ARNI has now been shown to further improve morbidity and mortality in HFrEF. • No proven therapies exist for improving prognosis in HFpEF. There is a need for therapeutic advances in patients with HFpEF. • The ongoing PARAGON-HF study evaluates the effect of LCZ696 in reducing the rate of the composite endpoint of CV death or total (first and recurrent) HF hospitalizations in patients with HFpEF. SELF assessment Questions 1-3 1. Mortality in patients with heart failure a) b) c) d) Is significantly higher in patients with HFrEF compared to HFpEF Is significantly higher in patients with HFpEF compared to HFrEF Has decreased significantly during the last 10 years Is similar between patients with HFrEF and patients with HFpEF 2. The threshold concentration for BNP that excludes HF for patients presenting with acute symptoms is: a) 100 pg/mL b) 120 pg/mL c) 300 pg/mL 3. The following treatment options reduce mortality in patients with HFpEF a) b) c) d) Diuretics Heart rate limiting calcium-channel blockers Beta-blockers None of the above Questions 4-5 4. The ESC guidelines recommend an incremental addition of treatment as HF progresses. According to Fonarow GC et al., patients who received a greater number of treatments at baseline were more likely a) to be alive at 24 months b) to be rehospitalised at 24 months c) to be rehospitalised at 12 months d) None of the above 5. Komajda et al showed that adherence of physicians to treatment guidelines is: a) b) c) d) a strong predictor of lower mortality a strong predictor of fewer CV hospitalisations a strong predictor of improved quality of life All of the above Questions 6-8 6. HF management can be improved by: a) b) c) d) Improving education and awareness among patients and health care professionals Optimising care pathways and cooperation between nurses and doctors Better implementation of evidence-based guideline recommendations All of the above 7. In the PARADIGM-HF study the following was not observed: a) LCZ696 was superior to ACE inhibition alone in reducing the risk of death and hospitalisation for HF b) More patients stopped their study medication because of adverse events in the LCZ696 group than in the enalapril group c) The Kaplan Meyer curves for the primary endpoint diverged early in the study d) The LCZ696 group had a higher proportion of patients with non-serious angioedema, but LCZ696 was not associated with an increase in serious angioedema 8. The PARAGON-HF study is evaluating a) The effect of LCZ696 in reducing CV death or HF hospitalisation in patients with HFrEF b) The effect of LCZ696 in reducing CV death or HF hospitalisation in patients with HFpEF c) The effect of LCZ696 in reducing CV death or HF hospitalisation in patients with HFpEF and HFrEF Answers 1d 2a 3d 4a 5b 6d 7b 8b