Hartfalendag 2020 Nieuwe middelen, nieuwe beloftes? Adriaan Voors, UMCG, Groningen University Medical Center Groningen
Hartfalendag 2020 Nieuwe middelen, nieuwe dilemma’s Adriaan Voors, UMCG, Groningen University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020 Disclosures • AAV received consultancy fees and/or research grants from: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Novonordisk, Roche Diagnostics • AAV is supported by a grant from the European Commission: FP7-242209- BIOSTAT-CHF • AAV is Clinical Established Investigator and supported by other grants of the Dutch Heart Foundation University Medical Center Groningen University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020 Nieuwe middelen, nieuwe dilemma’s • Dilemma 1: Sacubitril/valsartan 6 jaar na publicatie PARADIGM: ACE-remmers obsoleet? • Dilemma 2: SGLT-2 remmers na orkaan van studies: pas na optitratie ACE-ARNI/BB/MRA of basis therapie? • Dilemma 3: Is er nog een plaats voor vericiguat ? University Medical Center Groningen University Medical Center Groningen
Hartfalendag 2020 2011: Drugs Reducing Mortality in HFrEF Angiotensin Mineralocorticoid receptor Beta receptor ACE blocker blocker antagonist inhibitor 0% % Decrease in Mortality 10% 20% Drugs that inhibit the renin-angiotensin system 30% have modest effects on survival 40% Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF University Medical Center Groningen
Hartfalendag 2020 Sacubitril/Valsartan Doubles Effect on Cardiovascular Death of Current Inhibitors of the RAAS Angiotensin Angiotensin receptor ACE neprilysin blocker inhibition inhibitor 0% % Decrease in Mortality 15% 18% 10% 20% 20% 30% Effect of ARB vs placebo derived from CHARM-Alternative trial 40% Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial University Medical Center Groningen
Hartfalendag 2020 Recommendations Class Level Angiotensin receptor neprilysin inhibitor Sacubitril/valsartan is recommended as a replacement for an ACE-I to further reduce the risk of HF hospitalization and death in I B ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRA. 2016 ESC HF Guidelines Ponikowski, Voors et al. Eur J Heart Fail 2016 University Medical Center Groningen
Hartfalendag 2020 ARNI only after full ACE-ARB uptitration? University Medical Center Groningen
Hartfalendag 2020 PIONEER-HF • 881 HFrEF patients hospitalized for worsening HF • Both new-onset ADHF (67%) and acute-on-chronic HF (33%) • No background HF therapy mandated (<50% on ACEi/ARB) • After stabilization randomized to target dose of 2 dd 200 mg Sacubitril/Valsartan or 2 dd 10 mg enalapril • Primary outcome: change in NT-proBNP from baseline to week 4 and 8 Velazquez et al. NEJM 2018 University Medical Center Groningen
Hartfalendag 2020 PIONEER-HF: primary outcome Velazquez et al. NEJM 2018 University Medical Center Groningen
Hartfalendag 2020 PIONEER-HF: summary • Greater reduction in NT-proBNP • Reduced re-hospitalization for HF (8.0 vs. 13.8%; HR 0.56; p = 0.005) • Well tolerated with comparable rates of worsening renal function, hyperkalemia, symptomatic hypotension and angioedema. Velazquez et al. NEJM 2018 University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020 Nieuwe middelen, nieuwe dilemma’s • Dilemma 1: Sacubitril/valsartan 6 jaar na publicatie PARADIGM: ACE-remmers obsoleet? • Dilemma 2: SGLT-2 remmers na orkaan van studies: pas na optitratie ACE-ARNI/BB/MRA of basis therapie? • Dilemma 3: Is er nog een plaats voor vericiguat ? University Medical Center Groningen University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020 University Medical Center Groningen University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020 Nieuwe middelen, nieuwe dilemma’s • Dilemma 1: Sacubitril/valsartan 6 jaar na publicatie PARADIGM: ACE-remmers obsoleet? • Dilemma 2: SGLT-2 remmers na orkaan van studies: pas na optitratie ACE-ARNI/BB/MRA of basis therapie? • Dilemma 3: Is er nog een plaats voor vericiguat ? University Medical Center Groningen University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020 March 2020 University Medical Center Groningen University Medical Center Groningen
VERICIGUAT INCREASES sGC ACTIVITY TO IMPROVE Hartfalendag 2020 MYOCARDIAL AND VASCULAR FUNCTION Oxidative stress Decreased NO Endothelial dysfunction Decreased sGC activity Low NO availability Extracellular Vericiguat cGMP Increased Intracellular Increases cGMP production sCG sGC activity Heart Vasculature ↓ Progressive myocardial stiffening Arterial constriction ↓ ↓ Myocardial thickening ↓ Vascular stiffness ↓ Ventricular remodeling Fibrosis ↓ cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; sGC=soluble guanylate cyclase. 16 University Medical Center Groningen Heart Fail Rev. 2013;18:123-34.; Braunwald’s Heart Disease 2015; Handb Exp Pharmacol . 2009;191:485-506; Handb Exp Pharmacol. 2017;243:225-47; Heart Failure: A Companion to Braunwald’s Heart Disease 2020.
Hartfalendag 2020 Inclusion Criteria “Worsening “Chronic HF” after event” ▪ NYHA class II – IV ▪ Recent HFH or IV diuretic use ▪ LVEF < 45% ▪ With very elevated natriuretic ▪ On standard HF therapies peptides (BNP* or NT-proBNP) Patients may have been randomized as an inpatient or outpatient but must have met criteria for clinical stability (e.g., SBP ≥ 100 mmHg, off IV treatments ≥ 24 hours) 30 day screening period without run-in University Medical Center Groningen
Hartfalendag 2020 Primary Endpoint CV Death or HFH HR 0.90 (95% CI 0.82 – 0.98) P-value 0.019 University Medical Center Groningen
Hartfalendag 2020 University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020 VICTORIA Conclusions • VICTORIA enrolled a patient population with significant unmet needs not well addressed by prior HF studies • Vericiguat achieved clinically meaningful absolute primary event reduction of 4.2 / 100 patient-yrs • NNT for one year to prevent 1 primary outcome event is ~24 patients • Once-daily medicine, easy to titrate, generally safe and well tolerated, without monitoring of renal function or electrolytes University Medical Center Groningen University Medical Center Groningen
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