SLIDE 1
University Medical Center Groningen
University Medical Center Groningen
Nieuwe middelen, nieuwe beloftes? Adriaan Voors, UMCG, Groningen - - PowerPoint PPT Presentation
Nieuwe middelen, nieuwe beloftes? Adriaan Voors, UMCG, Groningen - - PowerPoint PPT Presentation
Hartfalendag 2020 Nieuwe middelen, nieuwe beloftes? Adriaan Voors, UMCG, Groningen University Medical Center Groningen Hartfalendag 2020 Nieuwe middelen, nieuwe dilemmas Adriaan Voors, UMCG, Groningen University Medical Center Groningen
SLIDE 2
SLIDE 3
University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020
University Medical Center Groningen
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
SLIDE 4
University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020
University Medical Center Groningen
- Dilemma 1: Sacubitril/valsartan 6 jaar na publicatie
PARADIGM: ACE-remmers obsoleet?
- Dilemma 2: SGLT-2 remmers na orkaan van studies: pas na
- ptitratie ACE-ARNI/BB/MRA of basis therapie?
- Dilemma 3: Is er nog een plaats voor vericiguat ?
Nieuwe middelen, nieuwe dilemma’s
SLIDE 5
Hartfalendag 2020
University Medical Center Groningen
Beta blocker Mineralocorticoid receptor antagonist ACE inhibitor Angiotensin receptor blocker
Drugs that inhibit the renin-angiotensin system have modest effects on survival 40%
Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF
0% 10% 20% 30% % Decrease in Mortality
2011: Drugs Reducing Mortality in HFrEF
SLIDE 6
Hartfalendag 2020
University Medical Center Groningen
10%
Sacubitril/Valsartan Doubles Effect on Cardiovascular Death of Current Inhibitors of the RAAS
20%
20%
30% 40%
ACE inhibitor Angiotensin receptor blocker
0% % Decrease in Mortality
18%
Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect
- f LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial
Angiotensin neprilysin inhibition
15%
SLIDE 7
University Medical Center Groningen
Hartfalendag 2020
2016 ESC HF Guidelines
Ponikowski, Voors et al. Eur J Heart Fail 2016
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 ambulatory patients with HFrEF who remain symptomatic despite
- ptimal treatment with an ACE-I, a beta-blocker and an MRA.
I B
SLIDE 8
University Medical Center Groningen
Hartfalendag 2020
ARNI only after full ACE-ARB uptitration?
SLIDE 9
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
SLIDE 10
University Medical Center Groningen
Hartfalendag 2020
PIONEER-HF: primary outcome
Velazquez et al. NEJM 2018
SLIDE 11
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
SLIDE 12
University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020
University Medical Center Groningen
- Dilemma 1: Sacubitril/valsartan 6 jaar na publicatie
PARADIGM: ACE-remmers obsoleet?
- Dilemma 2: SGLT-2 remmers na orkaan van studies: pas na
- ptitratie ACE-ARNI/BB/MRA of basis therapie?
- Dilemma 3: Is er nog een plaats voor vericiguat ?
Nieuwe middelen, nieuwe dilemma’s
SLIDE 13
University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020
University Medical Center Groningen
SLIDE 14
University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020
University Medical Center Groningen
- Dilemma 1: Sacubitril/valsartan 6 jaar na publicatie
PARADIGM: ACE-remmers obsoleet?
- Dilemma 2: SGLT-2 remmers na orkaan van studies: pas na
- ptitratie ACE-ARNI/BB/MRA of basis therapie?
- Dilemma 3: Is er nog een plaats voor vericiguat ?
Nieuwe middelen, nieuwe dilemma’s
SLIDE 15
University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020
University Medical Center Groningen
March 2020
SLIDE 16
University Medical Center Groningen
Hartfalendag 2020
16
VERICIGUAT INCREASES sGC ACTIVITY TO IMPROVE MYOCARDIAL AND VASCULAR FUNCTION
Extracellular
Intracellular sCG
↓ Progressive myocardial stiffening ↓ Myocardial thickening ↓ Ventricular remodeling ↓ Fibrosis ↓ Arterial constriction ↓ Vascular stiffness
Heart
cGMP
Vasculature
Increases sGC activity
Low NO availability
Increased cGMP production
cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; sGC=soluble guanylate cyclase.
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.
Vericiguat
Oxidative stress Endothelial dysfunction Decreased NO Decreased sGC activity
SLIDE 17
University Medical Center Groningen
Hartfalendag 2020
Inclusion Criteria
“Worsening event” “Chronic HF”
after
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) ▪ NYHA class II–IV ▪ LVEF < 45% ▪ On standard HF therapies ▪ Recent HFH or IV diuretic use ▪ With very elevated natriuretic peptides (BNP* or NT-proBNP) 30 day screening period without run-in
SLIDE 18
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
SLIDE 19
University Medical Center Groningen
Hartfalendag 2020
SLIDE 20
University Medical Center Groningen
Hartfalendag 2020 Hartfalendag 2020
University Medical Center Groningen
- 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