Hot messages from ESC London. Heart Failure Prof. Dr. Johann Bauersachs Klinik für Kardiologie und Angiologie

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1 Hot messages from ESC London Heart Failure 2015

2 Presenter Disclosure Information Hot messages from ESC London Heart Failure 2015 DISCLOSURE INFORMATION: The following relationships exist related to this presentation: Bayer, Novartis, Pfizer, Servier, Orion, Medtronic, Biotronik, Thoratec, Heartware

3 Heart Failure the magnitude of the problem Coronary deaths are down by half But heart failure has almost tripled Coronary Deaths Heart Failure Source: National Hospital Discharge Survey data. Centers for Disease Control and Prevention/National Center for Health Statistics and National Heart, Lung, and Blood Institute.

4 Heart Failure 2015 Eugene Braunwald The war against heart failure (LANCET 2015) Thomas Lüscher Heart failure the cardiovascular epidemic of the 21th century (EUROPEAN HEART JOURNAL 2015)

5 ESC Guideline Heart Failure 2012 Mineralocorticoid Receptor Antagonists (MRA) Diuretics to relieve symptoms / signs of congestion 2 Yes ACE inhibitor (or ARB if not tolerated) b ADD a MR antagonist b,d ADD a beta-blocker b Still NYHA class II-IV? McMurray et al., European Heart Journal 2012 ESC Recommendations Class a Level b An MRA is recommended for all patients with persisting symptoms (NYHA class II IV) and an EF 35%, despite treatment with an ACE inhibitor (or an ARB if an ACE inhibitor is not tolerated) and a betablocker, to reduce the risk of HF hospitalization and the risk of premature death. MRA underuse is mainly related to existing No or perceived c risk of hyperkalemia and/or worsening renal function. But: Patients at risk do profit from MRAs regarding clinical endpoints I A

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7 Finerenone versus eplerenone in patients with worsening heart failure and diabetes and/or chronic kidney disease ARTS-HF: Study Design Filippatos G, ESC London Sept 2015

8 ARTS-HF: Finerenone reduces all-cause death and cardiovascular hospitalizations Phase III study (FINESSE) will compare Finerenone with Eplerenone in patients with worsening heart failure and diabetes and/or kidney disease Filippatos G, ESC London Sept 2015

9 Williams B, ESC London Sept 2015

10 PATHWAY 2 Study demonstrated overwhelming efficacy of spironolactone in patients with resistant hypertension There is a high clinical need for novel MRAs with a better risk/benefit profile for the treatment of patients with heart failure, hypertension, diabetes, kidney disease Williams B, ESC London Sept 2015

11 TOPCAT (Spironolactone in HFpEF / diastolic heart failure) Heart failure hospitalisations In total cohort: Primary endpoint not significantly improved, but Significant reduction of heart failure hospitalisations American patients: (whose high event rate is representative of a HFpEF patient cohort): Significant improvement of primary endpoint Pitt et al., NEJM 2014

12 Is there an effect of Digoxin on mortality? Kotecha, ESC London Sept 2015; Ziff OJ et al, BMJ 2015

13 Perceived increase in mortality with Digitalis treatment is related to marked bias in non-randomised studies Kotecha, ESC London Sept 2015; Ziff OJ et al, BMJ 2015

14 DIGitoxin to Improve outcomes in patients with advanced chronic systolic Heart Failure multicenter, randomized, double blind, placebocontrolled trial Bavendiek, Bauersachs, DFG / BMBF Study program Intervention group: Standard of care (SOC) + digitoxin p.o. ( mg/die) Dose adjustment at 6 weeks and, if indicated, at 12 weeks after start of treatment. Target serum concentration of digitoxin preferably 8-18 ng/ml

15 Personal recommendations for Digitalis treatment in heart failure Patients with HFrEF (EF<35%) NYHA III-IV despite standard therapy with BB, ACE-I, MRA, and Ivabradine (if indicated) (Recurrent) heart failure hospitalisations Tachyarrhythmia despite betablocker (but no co-treatment digitalis/amiodarone!) Aim for lower dosage (target level Digoxin ng/ml) Control serum levels (especially during Digoxin treatment) Digitoxin instead of Digoxin in CKD and/or the elderly

16 A Phase 2b Trial Investigating the Efficacy and Safety of the Intracoronary Administration of AAV1/SERCA2a in Patients with Advanced Heart Failure CUPID 2 Background Greenberg B, ESC London Sept 2015

17 CUPID 2: No significant event reduction of AAV1/SERCA2a administration in patients with heart failure Greenberg B, ESC London Sept 2015

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19 Adaptive Servo-Ventilation (ASV)

20 SERVE-HF: Unexpected increase in cardiovascular mortality by adaptive servo ventilation in heart failure Primary Endpoint Time to first event of all-cause death, life-saving cardiovascular intervention*, or unplanned hospitalization for worsening chronic HF CONCLUSION: Patients with HFrEF and central sleep apnoea should not be treated with adaptive servo ventilation But: Patients with obstructive sleep apnoea were not included in SERVE-HV Cowie MR, ESC London Sept 2015, Cowie MR et al, New Engl J Med 2015

21 Implanted device-based impedance monitoring with telemedicine alerts on mortality and morbidity in heart failure OptiLink HF Study design Michael Böhm, ESC London Sept 2015

22 OptiLink-HF: device-based impedance monitoring with tele-medicine alerts does not improve mortality or morbidity in heart failure Michael Böhm, ESC London Sept 2015

23 Guideline based therapy for heart failure with reduced systolic left ventricular function (HFrEF) NYHA I NYHA II NYHA III NYHA IV HTX, LVAD CRT Ivabradine / digitalis glykosides Mineralocorticoid receptor antagonists (MRA) Diuretics Beta-Blockers ARNI ACE inhibitors (ARB) non-pharmacological therapies

24 Angiotensin receptor / neprilysin inhibition (ARNI) with LCZ696: Mechanisms of action LCZ696 Renin Angiotensin System Natriuretic Peptides Angiotensinogen Angiotensin I Valsartan Sacubitril (AHU377) Angiotensin II AT1 Receptor LBQ657 Neprilysin ANP BNP CNP Adrenomedullin Substance P Bradykinin Vasoconstriction Blood pressure increase Increased sympathicotonus Aldosterone increase Fibrosis Ventricular hypertrophy Berliner D, Bauersachs J, 2015 Inactive Fragments Vasodilatation Blood pressure lowering Reduced sympathicotonus Reduced aldosterone levels Natriuresis/Diuresis

25 25 PARADIGM-HF: ARNI vs. ACE inhibitor - summary of the results - 20 p<0.001 p<0.001 p<0.001 p<0,001 p<0.001 Events [%] p= Death from cardiovascular causes First hospitalization for worsening heart failure Death from any cause Symptomatic hypotension Serum creatinine 2.5 mg/dl Cough Berliner D, Bauersachs J, 2015 LCZ696 Enalapril

26 PARADIGM-HF: Study design Patients with symptomatic CHF Able to tolerate Enalapril 10 mg and LCZ mg LVEF < 35% BNP > 150 (100) pg/ml or NT-proBNP 600 (400) pg/ml Single-blind active run-in period Randomization n=8442 Double-blind Treatment period LCZ mg BID Enalapril 10 mg BID* LCZ mg BID LCZ mg BID Enalapril 10 mg BID Median of 27 months follow-up 2 Weeks 1 2 Weeks 2 4 Weeks On top of standard HFrEF therapy (excluding ACEIs and ARBs) McMurray et al. Eur J Heart Fail. 2013;, 2014;16:817 25; McMurray, et al. N Engl J Med 2014

27 BNP increases during treatment with LCZ696 (mechanism of action); for determination of prognosis during LCZ therapy only NT-proBNP is useful! 500 BNP 2,500 NT-proBNP 400 p<0.0001* p<0.0001* 2,000 p<0.0001* p<0.0001* pg/ml pg/ml 1,500 1, Entry Packer et al., Circ 2015 ENL LCZ 4 weeks 8 months Run-in Double-blind = median 0 Bars represent 25%/75% interquartile ranges for: LCZ696 Enalapril Entry ENL LCZ 4 weeks 8 months Run-in Double-blind

28 Hot messages from ESC London Heart Failure 2015 Spironolactone shows overwhelming efficacy for resistant hypertension in younger patients already treated with ACE-I/ARB, calcium antagonist and diuretic; may also be useful for HFpEF Optimisation of current medical treatment approaches for HFrEF (non-steroidal MRA Finerenone, Digitoxin) is promising Angiotensin receptor/neprilysin inhibitor (ARNI, LCZ 696) with proven efficacy over ACE inhibition is approved for HFrEF SERCA myocardial gene therapy was not effective in HFrEF Intrathoracic impedance and telemedicine-based heart failure disease management strategy was not effective in HFrEF Adaptive servoventilation in patients with HFrEF and central sleep apnoea did not reduce events and may be harmful

29 Heart Failure May, FLORENCE, Italy healthcare professionals 90+ countries represented 4 days of science abstracts and cases submitted 300+ expert faculty members 100+ scientific sessions 40+ industry sessions and workshops ESC/ HFA Guidelines on HEART FAILURE FOCUS ON: ACUTE HEART FAILURE «Heart failure: State of the Art»

30 Thank you for your attention!