Research burns bright

Rapidfireupdate: New heart failure therapies & late breaking trials for HFrEFand HFpEFJustin A. Ezekowitz, MBBChMSc FRCPC FACC FESC FAHAProfessor, University of AlbertaCo-Director, Canadian VIGOUR Centre Cardiologist, MazankowskiAlberta Heart InstituteMay somethingorother2019 •Available online: thecvc.caDisclosures / COI / RWI / RWA Research burns bright •….are no substitute for RCTPathophysiology and Epidemiology Step 1: Out with the antiquated….10 million leeches / year….NY Times 2017 Step 2: in with the new… Sacubitril / valsartan (HFpEF)PARAGON HF-PEF and sacubitril/valsartan Solomon, Lancet 2012 PARAMOUNTHF-PEF with elevated NPs No change in QOL Target patient population: ~4,800 patients with symptomatic HF (NYHA Class II–IV) and LVEF ³45% up to 2 weeks~240 weeks Valsartan 160 mg BID LCZ696 200 mg BIDLCZ696 100 mg BID On top of optimal background medications for co-morbidities (excluding ACEIs and ARBs) Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events) Valsartan 80 mg BID*Screening 3–8 weeks Active run-in periodDouble-blind treatment period PARAGON (HFpEF) SGLT2iEMPADAPASOTA Mechanisms with SGTL2 inhibitors Reduction of glucose and sodium Reduced sodium load Decreased systemic glucose load Decreased glucose trafficking and metabolism Reduction in blood pressure Improved endothelial functionReduced tissue sodium accumulation Super fuel hypothesis Evidence supporting potential mechanisms is sparseThere has been considerable discussion about three potential mechanisms •Improvements in hemodynamics•Super-fuel hypothesis•Improved oxygen delivery CV, cardiovascular; SGLT2, sodium-glucose cotransporter-2.MudaliarS, et al. Diabetes Care. 2016;39:1115–1122. Differences in study designs •CV, cardiovascular; CVD, cardiovascular disease; EF, ejection fraction; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; hHF, hospitalisationfor heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal proB-type natriuretic peptide; NYHA, New York Heart Association. 1. https://clinicaltrials.gov/ct2/show/record/NCT03036124. 2. https://clinicaltrials.gov/ct2/show/record/NCT03057977. DAPA-HF1 EMPEROR-Reduced2 SOLOIST-WHFPatient population•Patients with NYHA class II-IV heart failure with Reduced EF (<40%) and elevated NT-proBNP•eGFR ≥30mL/min/1.73 m2 •Diabetes and no Diabetes •Patients with NYHA class II-IV heart failure with Reduced EF (<40%) and elevated NT-proBNP•eGFR ≥20mL/min/1.73 m2•Diabetes and no diabetes •Patients with NYHA class II-IV heart failure with ANY EF and elevated NT-proBNP•eGFR ≥30mL/min/1.73 m2•Diabetes only•*hospitalSample sizeN=4500N=2850N=4000Study duration 33 months38 months32 months Primary outcomeTime to first occurrence of any component of the composite:•CV death •or hHF•or an urgent HF visit Time to the first occurrence of any of the components of the composite: •CV death •or hHF Time to the first occurrence of any of the components of the composite: •CV death •or hHF Secondary outcomes •Time to first occurrence of hHF•Time to first occurrence of CVD •Total number of hHFand CVD•Change in KCCQ at 8 months•Time to the composite of ≥5% decline in eGFR, reaching ESRD or renal death•All-cause mortality •Total number of hHF•eGFRslope change from baseline•Time to occurrence of sustained reduction of eGFR•Time to first hHF•Time to CVD•Time to all-cause mortality•Time to diabetes onset•Change in KCCQ at 12 months•Total all-cause hospitalisation •Total number of hHFinclrecurrent events•eGFR slope change from baseline•Time to occurrence of sustained reduction of eGFR•Time to first hHF•Time to CVD•Time to all-cause mortality•Change in KCCQ at 12 months•Total all-cause hospitalization•Above and EF<50% Soluble guanylate cyclase modulatorsVICTORIAVITALITY Different cGMP-augmenting pathways ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, c-type natriuretic peptide; NO, nitric oxide; PDE5, phosphodiesterase-5; pGC, particulate guanylyl cyclase; sGC, soluble guanylyl cyclase. modifiedafter Senniet al., EurHeart J. 2014 Oct 21;35(40):2797-815 EndothelialfunctionARNI Refs: C. Fiocchi: Am J Physiol1997, G769-G775 Fibroblasts Cardiomyocytes SMCs / VSMCs Vasodilation Antiproliferation Anti-inflammation Antifibrosis VERICIGUAT Soluble guanylate cyclase modulators HF-PEF and SGCm Fillipatos, EJHF 2017 Vericiguatvs placebo Improved QOLKCCQ –physical limitation scoreDose dependent VITALITY: Phase 2b RCT near completion % change from baseline -24.5%-23.3%-27.4%-29.8%-41.0% p=0.048p=0.15 -33.1% HFrEFand SGCmChange in NT-proBNPat 12 weeks (per protocol analysis) Gheorghiade, JAMA 2015 N=456 ptsHFrEF<45%Post D/c HF VICTORIA HFrEFEF<45%Post D/C HF FULLY ENROLLED OmecamtivmecarbilGALACTIC-HF •Direct cardiac myosin activator•Increases duration of systole by•Increasing entry rate of myosin into force-producing stateàincreasingoverall # of active cross-bridges•Increases stroke volume•No increase in MVO2 observed Omecamtiv mecarbil 1.TeerlinkJ. Heart Fail Rev. doi:10.1007/s10741-009-9135-0.2.Malik FI, et al. Science. 2011;331:1439-43. OmecamtivmecarbilΔStroke Volume(mL) ΔFractional Shortening(% points) ΔEjection Fraction(% points)Δ= placebo corrected change from baselineMean ±SEM 300 600 900 1200 -80 -40 0 40 80 120 160 Healthy Volunteers vs. Heart Failure Patients SET Heart Failure SET Healthy Volunteers [Omecamtiv mecarbil] (ng/mL) SET (msec) Change from Baseline ΔSET (msec)Cleland JGF, et al.Lancet 2011; 378: 676–83.Teerlink JR, et al.Lancet 2011; 378: 667–75. Healthy Volunteers -505101520 0481216 020406080100-404812 GALACTIC-HF IV IronHEART-FID •The prevalence of iron deficiency in HF is >40-50%–Ferritin <100 ng/mL–Ferritin 100-300 ng/mL + transferrin saturation [TSAT] <20%•In patients with and without anemia Iron Deficiency and HF JankowskaEA et al. EurHeart J. 2013 Mar;34(11):816-29. Mechanisms of Iron Deficiency Lewis GD. CircHF 2016 CONFIRM-HF Ponikowskiet al. EurHeart J. 2015 +33 ±11 m Improvements in NYHA class, PGA, QoL, with FCM was detected with statistical significance observed from Week 24 onwards Reduction in HF hospHR 0.39 (0.19-0.82)P = 0.009 HEART-FID Placebo + Standard of care (excluding IV iron) N ~ 3014Screening RANDOMIZATIONDay 0 1°endpoint:Mortality, HF hosp∆ 6MWD (6 mos) 3 mos6 mos 12 mos Ferric carboxymaltose(Dosing at Day 0 and Day 7 then every 6 mosas applicable) -28 days Patients with HFrEF, EF < 40%, iron deficiency (tsat<20%, ferritin < 100) *20+ sites across Canada Sometimes we don’t get it right in research:? Asked the wrong question? Engaged the wrong people? Lost in translation •MRAS in HFpEF, pragmatic trials–SPIRIT, SPIRRIT•Apelin peptides•VADs•SODIUM-HF•Gut microbiome•Telehomemonitoring / App-based management•Personalized medicine Other lines of research •>25000 patients in RCT underway•Future is bright •Sunrise not sunset for medical therapy Summary/Conclusions