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

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

Incremental Benefit of Neuroendocrine Activation in Moderate Heart Failure SOLVD Investigators, N Engl J Med 325 (1991): 293-302 ; CIBIS-II Investigators, Lancet 353 (1999): 9-13 ; MERIT-HF, Lancet 353 (1999): 2001-2007 ; Zannad et al, N Engl J Med 364 (2011): 11-21

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

Bayés-Genis et al, J Am Coll Cardiol 65 (2015): 657-665 AS-ag2-0415

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

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 40 30 20 HR: 0.80 (0.73, 0.87) p = 0.0000002 Enalapril 1117 (n=4212) LCZ696 (n=4187) 914 10 0 0 180 360 540 720 900 1080 1260 Days after Randomization At risk Enalapril: 4212 3883 3579 2922 2123 1488 853 236 LCZ696: 4187 3922 3663 3018 2257 1544 896 249 McMurray et al. N Engl J Med 2014;371:993 1004

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 = 0.00004 P = 0.00004 693 558 658 537 McMurray et al. N Engl J Med 2014;371:993 1004

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 < 0.0001 30 20 10 Enalapril (n=4212) LCZ696 (n=4187) 835 711 0 0 180 360 540 720 900 1080 1260 Days after Randomization McMurray et al. N Engl J Med 2014;371:993 1004

Desai et al, Circ Heart Fail 9 (2016): e002735 AS-ag1-0916

PARADIGM-HF: Safety LCZ696 (n=4187) Enalapril (n=4212) p value Hypotension (%) symptoms symptoms and SBP < 90 mmhg 14.0 2.7 9.2 1.4 < 0.001 <0.001 Renal impairment (%) Cr 2.5 mg/dl Cr 3.0 mg/dl 3.3 1.5 4.5 2.0 0.007 0.10 Hyperkalaemia (%) K + > 5.5 mmol/l K + > 6.0 mmol/l 16.2 4.3 17.4 5.6 0.15 0.007 Cough (%) 11.3 14.3 < 0.001

All-cause mortality (%) Italian Survey on Heart Failure In-hospital all-cause mortality according to systolic BP at admission 16 14 12 10 8 6 15.3% 7.8% 4 2 0 <119 120-139 4.1% 140-161 2.2% 161 Quartiles of SBP (mmhg) Tavazzi et al., Eur Heart J 27 (2006): 1207-1215 AS-av-0607

Restricted Cubic Splines Model for All-Cause Mortality According to On-Treatment BP Lee et al, JACC: Heart Failure 5 (2017): 810-819

Böhm et al, JACC: Heart Failure 5 (2017): 820-822

HF Drugs (ARNIs) Böhm et al, JACC: Heart Failure 5 (2017): 820-822

Primary Endpoint Böhm et al, Eur Heart J (2017): [doi:10.1093/eurheartj/ehw570] AS-an2-0217

Systolic Blood Pressure 4 Months after Baseline Böhm et al, Eur Heart J (2017): [doi:10.1093/eurheartj/ehw570] AS-ao1-0217

Systolic Blood Pressure 4 Months after Baseline Böhm et al, Eur Heart J (2017): [doi:10.1093/eurheartj/ehw570] AS-ao1-0217

Vardeny et al, Circ Heart Fail 11 (2018): e004745 AS-bh1-0418

Vardeny et al, Circ Heart Fail 11 (2018): e004745 AS-bh3-0418

Vardeny et al, Circ Heart Fail 11 (2018): e004745 AS-bh2-0418

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

Vardeny et al, Eur J Heart Fail (2016): [doi:10.1002/ejhf.580] AS-bd4-0616

Vardeny et al, Eur J Heart Fail (2016): [doi:10.1002/ejhf.580] AS-bd3-0616

BIOSTAT-CHF Ouwerkerk et al, Eur Heart J (2017): [doi:10.1093/eurheartj/ehx026]

PARADIGM-HF: Safety LCZ696 (n=4187) Enalapril (n=4212) p value Hypotension (%) symptoms symptoms and SBP < 90 mmhg 14.0 2.7 9.2 1.4 < 0.001 <0.001 Renal impairment (%) Cr 2.5 mg/dl Cr 3.0 mg/dl 3.3 1.5 4.5 2.0 0.007 0.10 Hyperkalaemia (%) K + > 5.5 mmol/l K + > 6.0 mmol/l 16.2 4.3 17.4 5.6 0.15 0.007 Cough (%) 11.3 14.3 < 0.001

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) 0.0276 (i) 50% decline in egfr 32/4187 (0.8) 42/4212 (1.0) 0.75 (0.47, 1.19) 0.2236 (iii) Reaching ESRD 8/4187 (0.2) 16/4212 (0.4) 0.50 (0.21, 1.16) 0.1057 AS-ac22-0615

Damman et al, J Am Coll Cardiol: Heart Failure (2018): [doi:10.1016/j.jchf.2018.02.004] AS-ac2-0518

PARADIGM-HF: Safety LCZ696 (n=4187) Enalapril (n=4212) p value Hypotension (%) symptoms symptoms and SBP < 90 mmhg 14.0 2.7 9.2 1.4 < 0.001 <0.001 Renal impairment (%) Cr 2.5 mg/dl Cr 3.0 mg/dl 3.3 1.5 4.5 2.0 0.007 0.10 Hyperkalaemia (%) K + > 5.5 mmol/l K + > 6.0 mmol/l 16.2 4.3 17.4 5.6 0.15 0.007 Cough (%) 11.3 14.3 < 0.001

Desai et al, JAMA Cardiol (2016): [doi:10.1001/jamacardio.2016.4733] AS-au1-0117

Desai et al, JAMA Cardiol (2016): [doi:10.1001/jamacardio.2016.4733] AS-au3-0117

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

Number PARADIGM-HF: cause / mode of death All causes CV causes Sudden Worsening HF Enalapril LCZ696 HR p = 0.84 < 0.001 0.80 0.00004 0.00008 0.80 0.008 0.79 0.034 AS-ab10-0615

Sudden death Desai et al, Eur Heart J (2015): [doi: 10.1093/eurheartj/ehv186] AS-aq3-0715

PARADIGM-HF: Emergency department visits for heart failure Enalapril LCZ696 (%) Proportion of patients HR 0.66 (0.52, 0.85) p = 0.001 Number of ER visits* RR 0.70 (0.52, 0.94) p = 0.017 Patients visiting ED Not leading to hospital admission *Includes repeat episodes ED Visits

Okumura et al, Circulation 133 (2016): 2254-2262 AS-aw1-0616

Okumura et al, Circulation 133 (2016): 2254-2262 AS-aw5-0616

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) 768 879 161 (3.8%) 229 (5.4%) P-value 0.87 (0.78, 0.98) P=0.019 0.82 (0.72, 0.94) P=0.005 0.69 (0.57, 0.85) P < 0.001 AS-ad16-0615

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

Vulnerable Phase: Does HR Drives mortality? First 30 days

Pre-Discharge Management: Targeting the Vulnerable Patient

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

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

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

PARADIGM-HF: Recurrent hospitalizations Enalapril LCZ696 Negative binomial model* Rate of admissions/patient/yr Enalapril 0.14 LCZ696 0.11 Rate ratio 0.77 (0.67, 0.89) P=0.0004 *Adjusted for treatment and region AS-ab26-0615

Pascual-Figal et al, ESC Heart Fail (2017): [doi:10.1002/ehf2.12246] AS-au-0318

Velazquez et al, Am Heart J 198 (2018): 145-151 AS-bg1-0418

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

Salomon et al., Circulation HF, 2017

Salomon et al., Circulation HF, 2017

Simpson et al., JACC 66: 2059-71, 2015

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

Kristensen et al, Circ Heart Fail 9 (2016): e002560 AS-aa13-0216

Kristensen et al, Circ Heart Fail 9 (2016): e002560 AS-aa17-0216

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:10.1016/ S2213-8587(17)30087-6]

Insulin Therapy Predicts Outcome Smooke et al, Am Heart J 149 (2005): 168-174 AS-bp-0608

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:10.1016/ S2213-8587(17)30087-6]

Giamouzis et al, Lancet Diab Endocrinol (2017): [doi:10.1016/s2213-8587(17)30089-x]

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)

Thank you for your attention! M. Böhm Klinik für Innere Medizin III Universitätsklinikum des Saarlandes Homburg/Saar, Germany michael.boehm@uks.eu