Pravin Manga Division of Cardiology Department of Medicine University of Witwatersrand

Pravin Manga Division of Cardiology Department of Medicine University of Witwatersrand

Overview Definition Epidemiology Biomarkers Treatment

Clinical Heart Failure: Syndrome in which patients have typical symptoms (breathlessness, ankle swelling and fatigue) and signs (elevated JVP, crepitations) resulting from an abnormality of cardiac structure and function Definition

Definition Heart Failure: Heart Failure Reduced EF : HF-REF EF 35% Grey Area EF 35-50% Heart Failure Preserved EF : HF-PEF EF 50% ESC guideline 2012

Definition Heart Failure: Heart Failure Reduced EF : HF-REF EF 35% Grey Area EF 35-50% Heart Failure Preserved EF : HF-PEF EF 50% ESC guideline 2012

Definition Heart Failure: Heart Failure Reduced EF : HF-REF EF 50% Heart Failure Preserved EF : HF-PEF EF 50% HeFSSA perspective on ESC guideline 2012. SAMJ 2013;103:661-667

Definition Clinical Heart Failure: Acute Chronic ESC guideline 2012

Discharges in thousands Heart failure is a major and growing public health problem Improvements in survival following MI, an aging population and increasing prevalence of risk factors such as hypertension may all contribute to an increasing prevalence of HF 1,2 700 600 500 400 300 200 100 0 Male Female 79 80 85 90 95 00 05 Years Hospital discharges for HF by sex (USA: 1979 2006). 3 HF=heart failure; MI=myocardial infarction 1. Hunt et al. J Am Coll Cardiol 2009;53:e1 90; 2. Dickstein et al. Eur Heart J 2008;29:2388 442; 3. Lloyd-Jones et al. Circulation 2010;121:e46 e215

Epidemiology Burden of HF doubles with every decade after age 40 Ageing population Burden of risk factors: Hypertension Diabetes IHD Obesity Rheumatic heart disease HIV

Patients have a poor prognosis following heart failure hospitalization

Cumulative probability of survival Cumulative probability of survival Outcomes for heart failure patients are poor in clinical practice HF mortality is high, with 50% of patients dying within 4 years of diagnosis and 40% of hospitalized patients dead or readmitted within 1 year 1 1.0 0.8 Female survival rates (%): Male survival rates (%): HF, MI and other malignancies 2 HF, MI and other malignancies 2 1.0 0.8 0.6 0.4 Breast MI 0.6 0.4 MI Bladder 0.2 0 Bowel Ovarian HF 0.2 0 Prostate Bowel HF Lung Lung 0 6 12 18 24 30 36 42 48 54 60 Month of follow-up 0 6 12 18 24 30 36 42 48 54 60 Month of follow-up All patients with a first admission to any Scottish hospital in 1991 for HF, MI or the four most common types of cancer specific to men and women were identified, and 5-year survival rates compared 2 1. Dickstein et al. Eur Heart J 2008;29:2388 442; 2. Stewart et al. Eur J Heart Fail 2001;3:315 22

Acute HF definition Acute HF is defined as rapid onset or change in the signs and symptoms of HF, resulting in the need for urgent therapy (ESC 1 ) development of acute or progressive symptoms of HF resulting in the need for hospitalization of the patient (ACC/AHA 2 ) 1 ESC Guidelines. Dickstein K, et al. Eur Heart J 2008;29:2388 442; 2 ACC/AHA Guidelines. Hunt SA, et al. J Am Coll Cardiol 2009;53:e1 90

AHF Physiopathology AHF is characterized by severe haemodynamic and neurohormonal abnormalities that may cause myocardial injury and/or renal dysfunction or may be a result of it AHF: Neurohormonal storm RASS activation Cytokine system activation Sympathetic hyperactivation

Overview Definition Epidemiology Biomarkers Treatment

pro-bnp (aa1-aa108) Cleavage NT-pro BNP (aa1-aa76) BNP (aa77-aa108)

Role of Biomarkers Where echocardiography is limited an alternative approach to diagnosis of HF is to measure BNP BNP < 100pg/ml or NT ProBNP <300 pg/ml in acute presentation excludes diagnosis of HF-REF ESC guideline 2012

Hazard ratio (95% confidence interval [CI]) BNP and NT-proBNP are markers of prognosis in chronic HF Increased levels of B-type natriuretic peptide (BNP) and N-terminal probnp (NTproBNP) are linked to worse outcomes in chronic HF 8 Mortality and morbidity 7 6 5 4 BNP NT-proBNP 3 2 1 0 1 (lowest) 2 3 4 5 6 7 8 9 10 Deciles (highest) Masson et al. Clin Chem 2006;52:1528 38

Change in BNP levels linked with change in mortality in HF patients BNP (pg/ml) 300 n=1370 250 200 High high Mortality (%) 25.4% 150 100 50 0 n=462 Low high n=229 High low n=1679 Low low 0 4 months 22.7% 12.8% 7.9% Latini R, et al. Am J Med 2006;119:70.e23-30

Overview Definition Epidemiology Biomarkers Treatment

Treatment goals in acute HF Current guidelines split treatment goals into: Immediate Relieve symptoms and stabilize the haemodynamic condition Intermediate Initiate pharmacological therapy and minimize length of hospitalization Long-term Prevent early re-hospitalization Improve Q of L

Current treatment of acute heart failure Treatment goals are to relieve dyspnoea and congestion Current standard of care is i.v. loop diuretics with or without nitrate vasodilators Current treatments do not have a strong evidence base Supporting evidence is derived from a single randomized clinical trials or from large non-randomized studies Dickstein et al. Eur Heart J 2008;29:2388 442

Dose Study Aimed to evaluate the safety and efficacy of various initial strategies of furosemide therapy in patients with ADHF Route of administration: Q12 hours bolus Continuous infusion Dosing Low intensification (1 x oral dose) High intensification (2.5 x oral dose)

Diuretic Strategies in Patients with Acute Decompensated Heart Failure G. Michael Felker, M.D., M.H.S., Kerry L. Lee, Ph.D., David A. Bull, M.D., Margaret M. Redfield, M.D., Lynne W. Stevenson, M.D., Steven R. Goldsmith, M.D., Martin M. LeWinter, M.D., Anita Deswal, M.D., M.P.H., Jean L. Rouleau, M.D., Elizabeth O. Ofili, M.D., M.P.H., Kevin J. Anstrom, Ph.D., Adrian F. Hernandez, M.D., Steven E. McNulty, M.S., Eric J. Velazquez, M.D., Abdallah G. Kfoury, M.D., Horng H. Chen, M.B., B.Ch., Michael M. Givertz, M.D., Marc J. Semigran, M.D., Bradley A. Bart, M.D., Alice M. Mascette, M.D., Eugene Braunwald, M.D., and Christopher M. O'Connor, M.D. for the NHLBI Heart Failure Clinical Research Network N Engl J Med 2011; 364:797-805

Change in Creatinine (mg/dl) Change in Creatinine at 72 hours 0.15 0.1 p = 0.45 p = 0.21 0.07 0.08 0.05 0.05 0.04 0 Q12 Continuous Low High

Proportion with Death, Rehosp, or ED Visit Proportion with Death, Rehosp, or ED visit Death, Rehospitalization, or ED Visit 0.6 HR for Continuous vs. Q12 = 1.19 95% CI 0.86, 1.66, p = 0.30 0.6 HR for High vs. Low = 0.83 95% CI 0.60, 1.16, p = 0.28 0.5 Continuous Q12 0.5 High Low 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 10 20 30 40 50 60 Days 0 0 10 20 30 40 50 60 Days

Cardiac and/or Renal Function AHF and Progression of HF Hospitalization Hypothesis: With each hospitalization, there is myocardial and or renal damage Hospitalization Hospitalization Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A) Time

Cardiac and/or Renal Function AHF and Progression of HF Identify triggers to decompensation Optimizing medical therapy Hospitalization Hospitalization Hospitalization Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A) Time

Newer Therapies Levosimendan Nesiritide Rolofyline Serelaxin Renin inhibition (aliskiren) is it an effective and safe alternative to/addition to ACE inhibition? Dual neprilysin/angiotensin receptor inhibitors efficacy and safety compared with an ACE inhibitor?

RELAXIN: A New Treatment for AHF

Relaxin Relaxin Peptide hormone Similar in size and shape to insulin (MW 5963) Found in men and women Normal hormone of pregnancy Benign safety profile

RELAX-AHF The Lancet, 2013; 381:29-39

RELAX-AHF The Lancet, 2013; 381:29-39

RELAX-II Can Seralaxin show mortality benefit in a large randomized phase 3 trial? The Lancet, 2013; 381:29-39

Definition Clinical Heart Failure: Acute Chronic

Guidelines recommend several core therapies for patients with chronic HF Therapy ACEIs Recommendation Recommended for patients with LVEF 40% to reduce risk of mortality and HF hospitalization (unless contraindicated or not tolerated) Class effect

Guidelines recommend several core therapies for patients with chronic HF Therapy ACEIs Recommendation Recommended for patients with LVEF 40% to reduce risk of mortality and HF hospitalization (unless contraindicated or not tolerated) ARBs Recommended in patients with LVEF 40% unable to tolerate ACEI therapy to reduce risk of mortality and HF hospitalization 36

Guidelines recommend several core therapies for patients with chronic HF Therapy β-blockers Recommendation Recommended for patients with LVEF 40% to reduce risk of mortality and HF hospitalization 37 Presentation Title Presenter Name Date Subject Business Use Only

Guidelines recommend several core therapies for patients with chronic HF Therapy β-blockers Recommendation Recommended for patients with LVEF 40% to reduce risk of mortality and HF hospitalization Carvedilol Bisoprolol Metoprolol 38 Presentation Title Presenter Name Date Subject Business Use Only

Guidelines recommend several core therapies for patients with chronic HF Therapy Aldosterone antagonists Recommendation Recommended for patients with persisting symptoms (NYHA class II IV) and LVEF 35%, despite treatment with an ACEI (or ARB if an ACEI is not tolerated) and a β- blocker, to reduce risk of mortality and HF hospitalization

Guidelines recommend several core therapies for patients with chronic HF Therapy Aldosterone antagonists Recommendation Recommended for patients with persisting symptoms (NYHA class II IV) and LVEF 35%, despite treatment with an ACEI (or ARB if an ACEI is not tolerated) and a β- blocker, to reduce risk of mortality and HF hospitalization Spironolactone Epleranone

PARADIGM-HF Study design Randomization Double-blind period Single-blind run-in period LCZ696 200 mg BID Enalapril 10 mg BID 2 weeks LCZ696 100 mg BID LCZ696 200 mg BID 1 2 weeks 2 4 weeks 1:1 randomization Enalapril 10 mg BID Primary endpoint: CV death or hospitalization for HF Study designed as a CV mortality trial sample size was determined by effect on CV mortality, not the primary endpoint Entry criteria: NYHA class II IV HF LVEF 40%, lowered to 35% in a protocol amendment BNP 150 pg/ml (NT-proBNP 600 pg/ml), OR BNP 100 pg/ml (NT-proBNP 400 pg/ml) and a hospitalization for HF within the last 12 months Stable on an ACEI or an ARB at a dose equivalent to enalapril 10 mg/day + β-blocker ± aldosterone antagonist Systolic BP 95 mmhg, egfr 30 ml/min/1.73 m 2 and serum potassium 5.4 meq/l at randomization 49

Physiological response NP system RAAS Pathophysiological response NPs Ang II Inactive fragments Neprilysin inhibitor Inactive fragments AT 1 receptor Vasodilation Vasoconstriction BP Sympathetic tone Aldosterone Fibrosis Hypertrophy Natriuresis/diuresis HF symptoms/ progression BP Sympathetic tone Aldosterone Fibrosis Hypertrophy

LCZ696 Physiological response NP system RAAS Pathophysiological response NPs Ang II Inactive fragments Neprilysin inhibitor Inactive fragments Valsartan AT 1 receptor Vasodilation Vasoconstriction BP Sympathetic tone Aldosterone Fibrosis Hypertrophy Natriuresis/diuresis HF symptoms/ progression BP Sympathetic tone Aldosterone Fibrosis Hypertrophy

PARADIGM-HF Baseline characteristics and conclusions 8,442 patients recruited at 985 sites in 47 countries Conclusions: Trial stopped early (March 2014) by the Data Monitoring Committee due to a significant drop in CV mortality in addition to the primary endpoint 52

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The End