Sacubitril/Valsartan unter der Lupe Subgruppenanalysen, real world data,

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1 Sacubitril/Valsartan unter der Lupe Subgruppenanalysen, real world data, praktische Erfahrungen M. Böhm Innere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin) Universitätsklinikum des Saarlandes Homburg/Saar

2 Incremental Benefit of Neuroendocrine Activation in Moderate Heart Failure SOLVD Investigators, N Engl J Med 325 (1991): ; CIBIS-II Investigators, Lancet 353 (1999): 9-13 ; MERIT-HF, Lancet 353 (1999): ; Zannad et al, N Engl J Med 364 (2011): 11-21

3 Regulation of Natriuretic Peptides, Bradykinin and Angiotensin II Angiotensin I Bradykinin ACE Angiotensin II Inactive products { Natriuretic peptides (ANP, BNP, CNP) NEP Inactive products Cardioprotection Hypertrophy Heart Vasodilation Vasoconstriction Sodium excretion Blood vessels Sodium Retention Kidney

4 Bayés-Genis et al, J Am Coll Cardiol 65 (2015): AS-ag2-0415

5 Concept of ARNIs : Pharmacologic Actions { Angiotensin I Bradykinin Natriuretic peptides (ANP, BNP, CNP) ACE Inhibition NEP Inhibition Angiotensin II Inactive products Inactive products Cardioprotection Hypertrophy Heart Böhm, unveröffentlicht Vasodilation Sodium excretion Vasoconstriction Blood vessels Sodium Retention Kidney

6 Cumulative Proportion of Patients with Primary End Point (%) PARADIGM-HF: Primary outcome Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial HR: 0.80 (0.73, 0.87) p = Enalapril 1117 (n=4212) LCZ696 (n=4187) Days after Randomization At risk Enalapril: LCZ696: McMurray et al. N Engl J Med 2014;371:

7 PARADIGM-HF Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial Death from CV causes 20% risk reduction HF hospitalization 21% risk reduction P = P = McMurray et al. N Engl J Med 2014;371:

8 Cumulative Proportion of Patients Who Died from Any Cause (%) PARADIGM-HF Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial Death from any cause 16% risk reduction 40 HR: 0.84 (0.76, 0.93) p < Enalapril (n=4212) LCZ696 (n=4187) Days after Randomization McMurray et al. N Engl J Med 2014;371:

9 Desai et al, Circ Heart Fail 9 (2016): e AS-ag1-0916

10 PARADIGM-HF: Safety LCZ696 (n=4187) Enalapril (n=4212) p value Hypotension (%) symptoms symptoms and SBP < 90 mmhg < <0.001 Renal impairment (%) Cr 2.5 mg/dl Cr 3.0 mg/dl Hyperkalaemia (%) K + > 5.5 mmol/l K + > 6.0 mmol/l Cough (%) < 0.001

11 All-cause mortality (%) Italian Survey on Heart Failure In-hospital all-cause mortality according to systolic BP at admission % 7.8% < % % 161 Quartiles of SBP (mmhg) Tavazzi et al., Eur Heart J 27 (2006): AS-av-0607

12 Restricted Cubic Splines Model for All-Cause Mortality According to On-Treatment BP Lee et al, JACC: Heart Failure 5 (2017):

13 Böhm et al, JACC: Heart Failure 5 (2017):

14 HF Drugs (ARNIs) Böhm et al, JACC: Heart Failure 5 (2017):

15 Primary Endpoint Böhm et al, Eur Heart J (2017): [doi: /eurheartj/ehw570] AS-an2-0217

16 Systolic Blood Pressure 4 Months after Baseline Böhm et al, Eur Heart J (2017): [doi: /eurheartj/ehw570] AS-ao1-0217

17 Systolic Blood Pressure 4 Months after Baseline Böhm et al, Eur Heart J (2017): [doi: /eurheartj/ehw570] AS-ao1-0217

18 Vardeny et al, Circ Heart Fail 11 (2018): e AS-bh1-0418

19 Vardeny et al, Circ Heart Fail 11 (2018): e AS-bh3-0418

20 Vardeny et al, Circ Heart Fail 11 (2018): e AS-bh2-0418

21 What Could you do better? - What else to do? - Reducing the dose?

22 Vardeny et al, Eur J Heart Fail (2016): [doi: /ejhf.580] AS-bd4-0616

23 Vardeny et al, Eur J Heart Fail (2016): [doi: /ejhf.580] AS-bd3-0616

24 BIOSTAT-CHF Ouwerkerk et al, Eur Heart J (2017): [doi: /eurheartj/ehx026]

25 PARADIGM-HF: Safety LCZ696 (n=4187) Enalapril (n=4212) p value Hypotension (%) symptoms symptoms and SBP < 90 mmhg < <0.001 Renal impairment (%) Cr 2.5 mg/dl Cr 3.0 mg/dl Hyperkalaemia (%) K + > 5.5 mmol/l K + > 6.0 mmol/l Cough (%) < 0.001

26 Renal progression: Conventional renal endpoint (post-hoc analysis) Post-hoc analysis based on conventional endpoint for renal disease progression (50% decline in egfr or reaching ESRD) Endpoint LCZ696 n/n (%) Enalapril n/n (%) Hazard Ratio (95% CI) P Value 2-sided Composite 37/4187 (0.9) 58/4212 (1.4) 0.63 (0.42, 0.95) (i) 50% decline in egfr 32/4187 (0.8) 42/4212 (1.0) 0.75 (0.47, 1.19) (iii) Reaching ESRD 8/4187 (0.2) 16/4212 (0.4) 0.50 (0.21, 1.16) AS-ac

27 Damman et al, J Am Coll Cardiol: Heart Failure (2018): [doi: /j.jchf ] AS-ac2-0518

28 PARADIGM-HF: Safety LCZ696 (n=4187) Enalapril (n=4212) p value Hypotension (%) symptoms symptoms and SBP < 90 mmhg < <0.001 Renal impairment (%) Cr 2.5 mg/dl Cr 3.0 mg/dl Hyperkalaemia (%) K + > 5.5 mmol/l K + > 6.0 mmol/l Cough (%) < 0.001

29 Desai et al, JAMA Cardiol (2016): [doi: /jamacardio ] AS-au1-0117

30 Desai et al, JAMA Cardiol (2016): [doi: /jamacardio ] AS-au3-0117

31 What Could you do better? - Arguments not to start? - My patient is stable! So why should I start?

32 Number PARADIGM-HF: cause / mode of death All causes CV causes Sudden Worsening HF Enalapril LCZ696 HR p = 0.84 < AS-ab

33 Sudden death Desai et al, Eur Heart J (2015): [doi: /eurheartj/ehv186] AS-aq3-0715

34 PARADIGM-HF: Emergency department visits for heart failure Enalapril LCZ696 (%) Proportion of patients HR 0.66 (0.52, 0.85) p = Number of ER visits* RR 0.70 (0.52, 0.94) p = Patients visiting ED Not leading to hospital admission *Includes repeat episodes ED Visits

35 Okumura et al, Circulation 133 (2016): AS-aw1-0616

36 Okumura et al, Circulation 133 (2016): AS-aw5-0616

37 PARADIGM-HF: Intensive care management Intensive management in hospital Number of patients requiring intensive care Total number of stays in intensive care Patients receiving IV positive inotropic drugs LCZ696 N=4187 n (%) Enalapril N=4212 n (%) 549 (13.1) 623 (14.8) (3.8%) 229 (5.4%) P-value 0.87 (0.78, 0.98) P= (0.72, 0.94) P= (0.57, 0.85) P < AS-ad

38 What Could you do better? - What else to do? - Why to start early?

39 Vulnerable Phase: Does HR Drives mortality? First 30 days

40 Pre-Discharge Management: Targeting the Vulnerable Patient

41 Early Benefit of LCZ696 HF Hospitalizations HR 0.69 (0.51, 0.92) p = 0.01 AS-ad8-0615

42 What Could you do better? - What else to do? - Shall I start in the hospital?

43 Time to First Event or All Event Patient 1 time Patient 2 time Patient 3 time Patient 4 time Patient 5 time Time to first event Hospitalization Death AS-ai5-0614

44 PARADIGM-HF: Recurrent hospitalizations Enalapril LCZ696 Negative binomial model* Rate of admissions/patient/yr Enalapril 0.14 LCZ Rate ratio 0.77 (0.67, 0.89) P= *Adjusted for treatment and region AS-ab

45 Pascual-Figal et al, ESC Heart Fail (2017): [doi: /ehf ] AS-au-0318

46 Velazquez et al, Am Heart J 198 (2018): AS-bg1-0418

47 What Could you do better? - Arguments not to start? - My patient is too sick and to start him is dangerous!

48 Salomon et al., Circulation HF, 2017

49 Salomon et al., Circulation HF, 2017

50 Simpson et al., JACC 66: , 2015

51 What Could you do better? - Arguments not to start? - My patient has comorbidities and to start him is dangerous too!

52 Kristensen et al, Circ Heart Fail 9 (2016): e AS-aa

53 Kristensen et al, Circ Heart Fail 9 (2016): e AS-aa

54 Changes in mean HbA1c and confidence intervals by treatment group at screening, randomisation, 1-year, 2-year, and 3-year visits Seferovic et al, Lancet Diab Endocrinol (2017): [doi: / S (17) ]

55 Insulin Therapy Predicts Outcome Smooke et al, Am Heart J 149 (2005): AS-bp-0608

56 Kaplan-Meier curve showing time to insulin initiation in the sacubitril/valsartan and enalapril groups, in patients previously not treated with insulin Seferovic et al, Lancet Diab Endocrinol (2017): [doi: / S (17) ]

57 Giamouzis et al, Lancet Diab Endocrinol (2017): [doi: /s (17)30089-x]

58 Implementation is important! Take Home Messages 1. - Innovation tested being superior against RAS blockade 2. - Obstacles: Low BP 3. - effective and safe at low BP 4. - Withdraw or reduce drugs not improving outcomes 5. - Check volume status, diuretic overdosing? 6. - No subgroup not responding (e.g. severity, major comorbidities)

59 Thank you for your attention! M. Böhm Klinik für Innere Medizin III Universitätsklinikum des Saarlandes Homburg/Saar, Germany