INIBITORI NEPRILISINA Marco Canepa, MD, PhD Università degli Studi di Genova Cardiologia, Ospedale Policlinico San Martino IRCCS marco.canepa@unige.it
ARNI: ANGIOTENSIN RECEPTOR NEPRILYSIN INHIBITORS ARNI SACUBITRIL SACUBITRILAT VALSARTAN Sing JSS et al. HEART 2017
Kaplan-Meier Estimates of Cumulative Rates (%) PARADIGM-HF Primary endpoint Cardiovascular Death or HF hospitalization Days After Randomization PARADIGM-HF. NEJM 2014
PARADIGM-HF Inclusion & Exclusion Criteria LVEF 35% STABLE DOSE of ACEi or ARB SYMPTOMATIC HYPOTENSION SBP <100 NYHA II-III INCREASED BNP or NT-proBNP egfr <30 K >5.2
PARADIGM-HF Characteristics at baseline PARADIGM-HF. NEJM 2014
PARADIGM-HF LVEF Solomon S et al. PARADIGM-HF. CIRC HF 2016
PARADIGM-HF Inclusion & Exclusion Criteria LVEF 35% STABLE DOSE of ACEi or ARB SYMPTOMATIC HYPOTENSION SBP <100 NYHA II-III BNP 150 or NTproBNP 600 egfr <30 K >5.2
PARADIGM-HF Inclusion & Exclusion Criteria LVEF 35% STABLE DOSE of ACEi or ARB SYMPTOMATIC HYPOTENSION SBP <100 NYHA II-III BNP 150 or NTproBNP 600 egfr <30 K >5.2
PARADIGM-HF SBP trends PARADIGM-HF. NEJM 2014
PARADIGM-HF Run-In Period & Study Period RUN-IN PERIOD STUDY PERIOD N=10521 N=9419 PARADIGM-HF. NEJM 2014
PARADIGM-HF Dropout during Run-In Period Desai et al. PARADIGM-HF. CIRC HEART FAIL 2016
PARADIGM-HF Dropout during Run-In Period Desai et al. PARADIGM-HF. CIRC HEART FAIL 2016
PARADIGM-HF Inclusion & Exclusion Criteria LVEF 35% STABLE DOSE of ACEi or ARB SYMPTOMATIC HYPOTENSION SBP <100 NYHA II-III BNP 150 or NTproBNP 600 egfr <30 K >5.2
PARADIGM-HF SBP trends PARADIGM-HF. NEJM 2014
PARADIGM-HF AEs and Discontinuation during Study McMurray JJ et al. PARADIGM-HF. NEJM 2014
PARADIGM-HF Dose Reduction in ARNI vs. ACEi group Participants with any dose reduction 42% in sacubitril/valsartan 43% in enalapril NS Vardeny et al. PARADIGM-HF. EUR J HEART FAILURE 2016
PARADIGM-HF Dose Reduction Predictors Vardeny et al. PARADIGM-HF. EUR J HEART FAILURE 2016
PARADIGM-HF Dose Reduction & Prognosis Cardiovascular Death or HF hospitalization Vardeny et al. PARADIGM-HF. EUR J HEART FAILURE 2016
PARADIGM-HF Dose Reduction & Prognosis ARNI vs. ACEi Cardiovascular Death or HF hospitalization Vardeny et al. PARADIGM-HF. EUR J HEART FAILURE 2016
PARADIGM-HF Inclusion & Exclusion Criteria LVEF 35% STABLE DOSE of ACEi or ARB SYMPTOMATIC HYPOTENSION SBP <100 NYHA II-III BNP 150 or NTproBNP 600 egfr <30 K >5.2
PARADIGM-HF Minimum required pre-study daily doses McMurray et al. PARADIGM-HF. EJHF 2013
PARADIGM-HF Inclusion & Exclusion Criteria LVEF 35% TARGET STABLE DOSE of ACEi or ARB SYMPTOMATIC HYPOTENSION SBP <100 NYHA II-III BNP 150 or NTproBNP 600 egfr <30 K >5.2
Pellicori P, Clark AL et al. EJHF 2017
Proportion of patients eligible for ARNI 1396 ambulatory CHF patients in UK 1. LVEF 40% at baseline 2. LVEF 40% at fup 3. Alive at fup 4. Available at fup 5. On target dose ACEi/ARB 6. No controindications 7. Symptoms 8. NTproBNP>400 9. NTproBNP>600 Pellicori P, Clark AL et al. EJHF 2017
Only 28% of the 5000 HFrEF patients in the ESC HF Long-Term Registry are at ACEi/ARB target dose - still up-titration - side effects (symptomatic hypotension and/or worsening renal function) - no obvious reason (>30%!) No loss of the advantage of sacubitril valsartan over enalapril for morbidity and mortality in >40% of patients in PARADIGM-HF who had doses reduction of trial medication during follow-up. Rather than going to the trouble of titrating patients to full dose ACEi/ARB and then switching to an ARNI, it may be appropriate to initiate patients on the latter from the outset. Pellicori P, Clark AL et al. EJHF 2017
AHA/ACC HF Guidelines. Focused Update 2017
Proportion of patients eligible for ARNI 1396 ambulatory CHF patients in UK 1. LVEF 40% at baseline 2. LVEF 40% at fup 3. Alive at fup 4. Available at fup On target dose ACEi/ARB 5. No controindications 6. Symptoms 7. NTproBNP>400 8. NTproBNP>600 Pellicori P, Clark AL et al. EJHF 2017
HIGH COSTS LOW LOW BENEFITS HIGH
Cost of one-month therapy with ARNI vs. ACEi/ARB 56 cp (bid) = 200 28 cp (od) = 5 28 cp (od) = 10
HIGH COSTS LOW LOW BENEFITS HIGH King et al. JACC HF 2014
PARADIGM-HF Inclusion & Exclusion Criteria LVEF 35% STABLE DOSE of ACEi or ARB SYMPTOMATIC HYPOTENSION SBP <100 NYHA II-III BNP 150 or NTproBNP 600 egfr <30 K >5.2
Natriuretic peptides in the prescription of ARNI Three major regulatory authorities [the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Institute for Health and Care Excellence (NICE)] have not suggested that initiation of sacubitril valsartan should be restricted to patients with an elevated NTproBNP. We believe this is a mistake. Natriuretic peptides are powerful prognostic markers. Low values will identify patients at low risk in whom sacubitril valsartan is unlikely to be cost-effective. Even if the relative reduction in risk is similar, patients at low risk of events will have a small absolute benefit. Pellicori P, Clark AL et al. EJHF 2017; Van Veldhuisen et al. JACC 2013
Death and HF hospitalization Van Veldhuisen et al. JACC 2013; AHA/ACC 2017 HF Guidelines update
Natriuretic peptides in the prescription of ARNI In our opinion, measuring plasma natriuretic peptides would be a simple, effective and probably cost-effective strategy that would reduce prescriptions of sacubitril valsartan for patients who had little to gain and greatly increase them in those most likely to benefit. We predict that this would lead to an overall increase in sacubitril valsartan use but, importantly, a greater increase in what we consider appropriate use. Pellicori P, Clark AL et al. EJHF 2017; Van Veldhuisen et al. JACC 2013
PARADIGM-HF Inclusion & Exclusion Criteria LVEF 35% STABLE DOSE of ACEi or ARB SYMPTOMATIC HYPOTENSION SBP <100 NYHA II-III BNP 150 or NTproBNP 600 egfr <30 K >5.2
SELECTING THE RIGHT PATIENTS FOR ARNI YES HFrEF patients with LVEF 35% NYHA II-III & increased BNP/NT-proBNP SBP>100 mmhg Tolerating target ACEi/ARB MAYBE On low-dose ACEi/ARB ACEi/ARB naïve NO DATA NYHA IV/stage D HF Hospitalized HF HFpEF NYHA I/asymptomatic LVH
ARNI UPCOMING CLINICAL STUDIES A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients (PARALLAX) Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) comparison Of Sacubitril/valsartaN Versus Enalapril on Effect on ntpro-bnp in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF) www.clinicaltrials.gov Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) ARNI in Asymptomatic Patients With Elevated Natriuretic Peptide and Elevated Left Atrial Volume Index elevation (PARABLE) Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event (TRANSITION)
TITRATION CONSERVATIVE vs. CONDENSED initiation CONSERVATIVE CONDENSED Senni et al. TITRATION. EUR J HEART FAILURE 2016
ARNI Efficacy According to Age Jhund PS et al. PARADIGM-HF. EUR HEART J 2015
Shen et al. NEJM 2017
THE BUILDING BLOCKS OF HFrEF THERAPY
MORTALITY/YEAR TODAY PROGNOSIS OF CHRONIC HFrEF 10% TOTAL MORTALITY 5% COMORBIDITIES SUDDEN DEATH 1990 1995 2000 2005 2010 2015 TODAY