Improving outcomes in heart failure with reduced EF

Transcription

1 Improving outcomes in heart failure with reduced EF Justin A. Ezekowitz, MBBCh MSc FRCPC FACC FESC FAHA Associate Professor, University of Alberta Co-Director, Canadian VIGOUR Centre Cardiologist, Mazankowski Alberta Heart Institute 6 June 2015

2 Disclosures Available online: vigour.ualberta.ca

3 New Technology or Innovations can be disruptive

4

5 HF Reduced ejection fraction Current GDMT (ACE or ARB, BB and MRA) reduces the risk of mortality, hospitalization and improves quality of life Multiple, adequately powered RCT Residual risk despite GDMT

6 HF REF: the R is for Risk Annualized mortality rate: NYHA 2* = 7% Outpatient HF in Alberta = 7.5% CHFN = 15% SHFM average Alberta HF patient: On ACE/BB/MRA = 5% Not ACE/BB/MRA = 14%

7 PART 1: HEART RATE

8 Heart Rate α Longevity? Basal O 2 consumption / atom = 10 O 2 / lifetime / atom O 2 consumption / heart beat = 10-8 O 2 / heart beat Levine, JACC 1997

9 Heart rate and the CV Center

10 A word of caution Heart rate measurement varies Studies have included: Patient / Physician / Nurse / Research Assistant ECG / Holter / BP machine Mean measurements (average of >1 ) With or without rest period Heart rate before, during or after exercise Iphones,

11 Coherence: HR and physical fitness Copenhagen Healthy males Resting ECG N= years Jensen Heart 2013

12 Mechanism: HR on the substrate Elevated heart rate Atherosclerosis Endothelial dysfunction Oxidative stress Plaque stability Arterial stiffness + + Chronic HF Oxygen demand efficiency stiffness + + Ischemia Oxygen consumption Duration of diastole Coronary perfusion LV Remodeling Cardiac hypertrophy Slide courtesy of

13 Ivabradine: pure heart rate reduction closed open closed RR 0 mv Pure heart rate reduction -40 mv -70 mv Ivabradine I f inhibition reduces the diastolic depolarization slope, thereby lowering heart rate Thollon C, et al. Brit J Pharmacol. 1994;112:37-42.

14 SHIFT: inclusion Class II to IV NYHA heart failure Ischemic/non-ischemic etiology LV systolic dysfunction (EF 35%) Heart rate 70 bpm Sinus rhythm Documented hospital admission for worsening heart failure 12 months Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

15 SHIFT: Design Ivabradine 5 mg bid Ivabradine 7.5/5/2.5 mg bid according to HR and tolerability Matching placebo, bid D0 D14 D28 M4 Every 4 months 3.5 years Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

16 Background Beta-blocker Treatment Patients (%) Ivabradine Placebo BB at randomization At least 50% target daily dose Target daily dose Swedberg K, et al. Lancet

17 SHIFT: Mean Heart Rate Reduction Heart rate (bpm) 90 70% of patients on ivabradine 7.5 mg bid Placebo Ivabradine 50 Swedberg K, et al. Lancet weeks Months

18 SHIFT: Primary Composite Endpoint Cumulative frequency (%) HR = 0.82 ( ) P < Placebo 18% 20 Ivabradine 10 Swedberg K, et al. Lancet Months

19 SHIFT: Hospitalization for HF Cumulative frequency (%) 30 HR = 0.74 ( ) P < Placebo 26% 20 Ivabradine 10 Swedberg K, et al. Lancet Months

20 SHIFT: Cardiovascular Death Cumulative frequency (%) 30 HR = 0.91 ( ) P = Placebo 10 Ivabradine Swedberg K, et al. Lancet Months

21 SHIFT: Death from Heart Failure Cumulative frequency (%) 10 HR = 0.74 ( ) P = Placebo 26% Ivabradine Swedberg K, et al. Lancet Months

22 CCS Recommendation Practical tip At present, ivabradine has not yet been approved for clinical use in Canada. When ivabradine does become available, the results of SHIFT will likely support the use of ivabradine in patients with moderate to severe HF on optimum medical therapy including β-blockade with LVEF 35% and resting heart rate 70 bpm

23 PART 2: ARNI

24 NEP and NEP inhibition Relative affinity for NEP ANP and CNP Ang II Ang I Adrenomedullin Substance P Bradykinin Endothelin BNP NEP Inactive fragments or metabolites NEPi by itself: Angiotensin-2 ET-1 Bradykinin cgmp Sodium excretion Fibrosis LVH Fryer BJP

25 Seriously, I just learned about BNP and now there are other letters of the alphabet soup of NPs that are important? Cardiomyocytes 1 Endothelial cells 1 ANP and BNP CNP NPR-A NPR-B NPR-C GTP cgmp GTP cgmp Internalization Receptor recycling Vasodilation 1,2 Antihypertrophy 1,2 Antiproliferation 2 Vascular regeneration 1 Myocardial relaxation 1 Diuresis, natriuresis 1,2 Antiapoptosis 1 Anti-aldosterone 1,2 Renin secretion inhibition 1,3 Reduced sympathetic tone 4 Lipolysis 1 Vasodilation 1,2 Antihypertrophy 1,2 Antiproliferation 2 Vascular regeneration 1 Venodilation 1 Antifibrosis 1 Degradation of NPs 1,2,5 1. Mangiafico et al. Eur Heart J 2013;34:886 93; 2. Gardner et al. Hypertension 2007;49:419 26; 3. Pandey. J Am Soc Hypertens 2008;2:210 26; 4. Levin et al. NEngl J Med1998;339;321 8; 5. Von Lueder et al. Pharmacol Ther 2014 [Epub ahead of print]

26 LCZ696 and VPI Bradykinin breakdown Omapatrilat inhibits ACE, APP and NEP LCZ696 inhibits only NEP Active bradykinin Active bradykinin ACE APP NEP DPP-4 Inactive bradykinin Inactive bradykinin Fryer BJP

27 Vardeny CPT 2013

28 PARADIGM-HF International, multi-center, double-blind, placebo-controlled RCT Randomization, 1:1 LCZ mg BID Enalapril 10 mg BID Primary: composite of CV death from or hospitalization for HF McMurray NEJM 2014

29 PARADIGM-HF: Eligibility criteria Inclusion: NYHA II-IV HF LVEF 40 % [ 35% amend] Elevated NPs BNP 150 pg/ml NT-proBNP 600 pg/ml Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists Inclusion (cont) Any ACEi or ARB, but able to tolerate stable dose equivalent to at least enalapril 10 mg daily for at least 4 weeks Major Exclusion: SBP < 95 mmhg egfr <30 ml/min/1.73 m 2 K > 5.4 meq/l McMurray NEJM 2014

30 PRADIGM-HF: Prior ACE / ARB Dose

31 PARADIGM-HF: Design Single-blind run-in period Double-blind period LCZ mg BID Enalapril LCZ696 Rand n 10 mg BID 100 mg BID 200 mg BID Enalapril 10 mg BID 2 weeks 1-2 weeks 2-4 weeks N=1102 N=977 N=8399 patients McMurray NEJM 2014

32 PARADIGM-HF: Baseline chars. LCZ696 (n=4187) Enalapril (n=4212) Age (years) 63.8 ± ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± ± 6.3 NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9% Systolic blood pressure (mm Hg) 122 ± ± 15 Heart rate (beats/min) 72 ± ± 12 N-terminal pro-bnp (pg/ml) 1631 ( ) 1594 ( ) B-type natriuretic peptide (pg/ml) 255 ( ) 251 ( ) History of diabetes 35% 35% Beta-adrenergic blockers 93.1% 92.9% Mineralocorticoid antagonists 54.2% 57.0% ICD and/or CRT 16.5% 16.3% McMurray NEJM 2014

33 PARADIGM-HF: Primary endpoint Kaplan-Meier Estimate of Cumulative Rates (%) Patients at Risk LCZ696 Enalapril 8 0 Enalapril (n=4212) Days After Randomization LCZ696 (n=4187) HR = 0.80 ( ) P = Number needed to treat = 21 Primary = CV death or HF Hospitalization McMurray NEJM 2014

34 32 PARADIGM-HF: CV death Kaplan-Meier Estimate of Cumulative Rates (%) HR = 0.80 ( ) P = Number need to treat = 32 Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril Days After Randomization McMurray NEJM

35 PARADIGM-HF: All cause mortality Kaplan-Meier Estimate of Cumulative Rates (%) HR = 0.84 ( ) P< Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril McMurray NEJM 2014

36 PARADIGM-HF: Safety endpoints LCZ696 (n=4187) Enalapril (n=4212) P Value Prospectively identified adverse events Symptomatic hypotension < Serum potassium > 6.0 mmol/l Serum creatinine 2.5 mg/dl Cough < Discontinuation for adverse event Discontinuation for hypotension NS Discontinuation for hyperkalemia NS Discontinuation for renal impairment Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise McMurray NEJM 2014

37 PARADIGM-HF: Sec. Analyses Reduction in SCD by 20% Will this reduce need for referral for ICD? Reduction in repeat ED, repeat hosps and ICU days and visits Will this drive the cost-effectiveness? Improved NYHA class Less decline in QOL (by 8 months) Will this be the key for patients? Packer, Circulation 2015

38 HF Reduced ejection fraction Recommendation We recommend that in patients with mild to moderate HF, an EF <40%, an elevated natriuretic peptide level or hospitalization for HF in the last 12 months, a serum potassium < 5.2 mmol/l and an egfr 30 ml/min and treated with appropriate doses of guideline-directed medical therapy should be treated with LCZ696 in place of an ACE inhibitor or an ARB, with close surveillance of serum potassium and creatinine. Conditional Recommendation, High Quality of Evidence Values and Preferences This recommendation places high value on medications proven in large trials to reduce mortality, HF rehospitalization and symptom. It also considers the health economic implications of new medications. The recommendation is conditional because the drug is not yet approved for clinical use in Canada and the price is still not known. CCS HF Guidelines, Moe, Ezekowitz, et al CJC 2014

39 GDMT at a reasonable dose is first step; don t forget the basics The anatomy of a recommendation NYHA 2-3 Recommendation We recommend that in patients with mild to moderate HF, an EF <40%, an elevated natriuretic peptide level or hospitalization for HF in the last 12 months, a serum potassium < 5.2 mmol/l and an egfr 30 ml/min and treated with appropriate doses of guideline-directed medical therapy should be treated with LCZ696 in place of an ACE inhibitor or an ARB, with close surveillance of serum potassium and creatinine. Conditional Recommendation, High Quality of Evidence Pending HC approval EF < 40% until amendment to <35%; no difference on primary endpoint HQ RCT Adeq powered NPs mostly not available in Canada as outpt; no interaction of either of these on outcome so anticipate this may be changed in future

40 HF-REF in development Soluble guanylate cyclase Vericiguat SOCRATES Mineralocortocoid antag s Finerenone ARTS Devices CRT, mems many Sarcomere-inotropes Omecamtiv COSMIC Guided Rx NT-proBNP GUIDE-IT Diet Low sodium SODIUM-HF* Supplements CoQ10 (name pending) Supplements Resveratrol REV-HF*

41 Summary Heart rate and RAAS remain important Ivabradine will be a new addition for some patients NEPi takes advantage of NP system ARNI (LCZ696) will replace ACE/ARB for some patients

42 Acknowledgements

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44 Key references 1. McMurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., et al. (2014). Angiotensin Neprilysin Inhibition versus Enalapril in Heart Failure. The New England Journal of Medicine, doi: /nejmoa mcmurray, J. J. V., 2. Packer, M., Desai, A. S., Gong, J., Lefkowitz, M., Rizkala, A. R., et al. (2014). Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). European Journal of Heart Failure, 16(7), doi: /ejhf Packer, M., McMurray, J. J. V., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., et al. (2015). Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation, 131(1), doi: /circulationaha McMurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., et al. (2013). Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). European Journal of Heart Failure, 15(9), doi: /eurjhf/hft052

45 HF reduced ejection fraction Cumulative reduction in the odds of death over 2 years compared with no treatment Fonarow G C et al. J Am Heart Assoc 2012;1:16-26

46 Other RAS blockers RAS blockade: Renin inhibitors: No additional benefit Omapatrilat: IMPRESS: n=573 pts, 12 weeks omapatrilat fewer events than lisinopril OVERTURE: enalapril and omapatrilat similar event rate Angioedema signal: 2.1% in black, 0.5% in non-black patients Other agents on cutting room floor: samipatrilat, gemopatrilat, MDL , fasidotril, z-13752a IMPRESS, Lancet 2000 OVERTURE, circ 2002