Late-breaking Heart Failure Trials 2.0Justin A. Ezekowitz, MBBChMSc FRCPC FACC FESC FAHAProfessor, University of AlbertaCo-Director, Canadian VIGOUR Centre Cardiologist, MazankowskiAlberta Heart InstituteZoomDay2020

Late-breaking Heart Failure Trials 2.0Justin A. Ezekowitz, MBBChMSc FRCPC FACC FESC FAHAProfessor, University of AlbertaCo-Director, Canadian VIGOUR Centre Cardiologist, MazankowskiAlberta Heart InstituteZoomDay2020 •Available online: thecvc.ca•VICTORIA: Executive Committee Disclosures / COI / RWI / RWA •VICTORIA Primary•DAPA-HF NT-proBNP•GALACTIC Baseline ACC 2020 ShelleyJonathan SeanNadiaSerge ChrisStephanie Mona Michael VICTORIA (sGC) Soluble Guanylate Cyclase (sGC) Intracellular Extracellular cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; PDE5=phosphodiesterase 5; RAAS=renin-angiotensin-aldosterone system; sGC=soluble guanylate cyclase; SNS=sympathetic nervous system. 1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2. Buys ES et al. Cardiovasc Res. 2008;79(1):179-186. 3. GheorghiadeM et al. Heart Fail Rev. 2013;18(2):123-134. 4. Data on file. N O Increased oxidative stress Soluble Guanylate Cyclase (sGC) Intracellular Extracellular N O N O Increased oxidative stress Low NO availability N O cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; PDE5=phosphodiesterase 5; RAAS=renin-angiotensin-aldosterone system; sGC=soluble guanylate cyclase; SNS=sympathetic nervous system. 1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2. Buys ES et al. Cardiovasc Res. 2008;79(1):179-186. 3. GheorghiadeM et al. Heart Fail Rev. 2013;18(2):123-134. 4. Data on file. Soluble Guanylate Cyclase (sGC) sGC N O Intracellular Extracellular N O N O Increased oxidative stress Low NO availability Decreased sGC stimulation N O cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; PDE5=phosphodiesterase 5; RAAS=renin-angiotensin-aldosterone system; sGC=soluble guanylate cyclase; SNS=sympathetic nervous system. 1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2. Buys ES et al. Cardiovasc Res. 2008;79(1):179-186. 3. GheorghiadeM et al. Heart Fail Rev. 2013;18(2):123-134. 4. Data on file. Soluble Guanylate Cyclase (sGC) sGC N O Intracellular Extracellular cGMP N O N O Increased oxidative stress Low NO availability Decreased sGC stimulation Decreased cGMP production N O cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; PDE5=phosphodiesterase 5; RAAS=renin-angiotensin-aldosterone system; sGC=soluble guanylate cyclase; SNS=sympathetic nervous system. 1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2. Buys ES et al. Cardiovasc Res. 2008;79(1):179-186. 3. GheorghiadeM et al. Heart Fail Rev. 2013;18(2):123-134. 4. Data on file. Soluble Guanylate Cyclase (sGC) sGC N O PDE5 Intracellular Extracellular cGMP Increased oxidative stress Low NO availability Decreased sGC stimulation Decreased cGMP production N O N O N O cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; PDE5=phosphodiesterase 5; RAAS=renin-angiotensin-aldosterone system; sGC=soluble guanylate cyclase; SNS=sympathetic nervous system. 1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2. Buys ES et al. Cardiovasc Res. 2008;79(1):179-186. 3. GheorghiadeM et al. Heart Fail Rev. 2013;18(2):123-134. 4. Data on file. Soluble Guanylate Cyclase (sGC) N O Increased oxidative stress •Progressive myocardial dysfunction•Adverse left-ventricular remodeling•Vascular dysfunction•Increased fibrosis•Increased inflammation Low NO availability sGC N ODecreased sGC stimulation Decreased cGMP production PDE5 cGMP N O N O Intracellular Extracellular Clinical Effects of an Impaired sGC-cGMP Pathway Oxidative stress and the resulting deficiency in NO can lead to insufficient stimulation of the sGC, decreased production of cGMP , and subsequent cardiovascular dysfunction and HF1,3 cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; PDE5=phosphodiesterase 5; RAAS=renin-angiotensin-aldosterone system; sGC=soluble guanylate cyclase; SNS=sympathetic nervous system. 1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2. Buys ES et al. Cardiovasc Res. 2008;79(1):179-186. 3. GheorghiadeM et al. Heart Fail Rev. 2013;18(2):123-134. 4. Data on file. 13 sGC not targeted by current Rx cGMP=cyclic guanosine monophosphate; HF=heart failure; LV=left ventricular; MOA=mechanism of action; NO=nitric oxide; PDE5=phosphodiesterase type 5; sGC=soluble guanylate cyclase.1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2.MünzelT et al. Circulation. 2011;123(19):2132-2144. 3. Watanabe H et al. J Am Coll Cardiol. 1998;32(5):1194-1200. 4. Michalak M et al. CircHeartFail. 2018;11(3):e004813. NO sGC cGMP PDE5 Nitrates2,3 PDE5 inhibitors1,4 MOAUpstream of sGC-cGMP2 BenefitImproved LV function and exercise capacity in combination with hydralazine2 Challenge•Development of tolerance3•Confirmatory data lacking MOADownstream of sGC-cGMP4BenefitMitigates myocardial remodeling4 ChallengePDE5 is dependent on NO-sGC activity and cGMP production—often impaired in HF1 The impact of nitrates and PDE5 inhibitors is limited, and they do not directly stimulate sGC sGC and HF: vericiguat cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; PDE5=phosphodiesterase type 5; sGC=soluble guanylate cyclase. 1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2. Buys ES et al. Cardiovasc Res. 2008;79(1):179-186. 3. GheorghiadeM et al. Heart Fail Rev. 2013;18(2):123-134. 4. Data on file. N O Increased oxidative stress Low NO availability sGC N O Decreased sGC stimulation Decreased cGMP production PDE5 cGMP N O N O Intracellular Extracellular Clinical Effects of an Impaired sGC-cGMP Pathway •Progressive myocardial dysfunction•Adverse left-ventricular remodeling•Vascular dysfunction•Increased fibrosis•Increased inflammation sGC and HF: vericiguat cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; PDE5=phosphodiesterase type 5; sGC=soluble guanylate cyclase.1. BreitensteinS et al. HandbExp Pharmacol. 2017;243:225-247. 2. Buys ES et al. Cardiovasc Res. 2008;79(1):179-186. 3. GheorghiadeM et al. Heart Fail Rev. 2013;18(2):123-134. 4. Armstrong PW et al. JACC Heart Fail. 2018;6(2):96-104. N O Increased oxidative stress •Improvedmyocardial function•Reducedleft-ventricular remodeling•Improvedvascular function•Decreasedfibrosis•Decreasedinflammation Low NO availability IncreasedNO sensitivity &sGC stimulation IncreasedcGMP production N O N O Vericiguatdirectly and selectively stimulates sGC to increase cGMP production even under low-NO conditions in HF4 cGMP sGC N O Vericiguat Intracellular Extracellular PDE5 Clinical Effects of Vericiguaton an Impaired sGC-cGMP Pathway VICTORIA Placebo Vericiguat Event-driven study durationEstimated median follow-up 18 months Up-titration at 2-week intervals CV=cardiovascular; EF=ejection fraction; eGFR=estimated glomerular filtration rate; EQ-5D=EuroQol5-dimension; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; IV=intravenous; KCCQ=Kansas City Cardiomyopathy Questionnaire; NYHA=New York Heart Association; QD=once daily; QoL=quality oflife; SBP=systolic blood pressure.1. Armstrong PW et al. JACC Heart Fail.2018;6(2):96-104. 2. Clinicaltrials.gov. NCT02861534. Accessed April 9, 2019. N=4872Worsening chronic HFrEF population:•EF <45%•NYHA II-IV•Prior HF hospitalization or outpatient IV diuretic for HF•Elevated natriureticpeptides •SBP ≥100 mmHg•eGFR ≥15 mL/min/1.73 m2 2.5 mg QD5 mg QD10 mg QD Primary endpoint: Composite of CV death or hospitalization for HFSecondary endpoints: •Time to CV death•Time to first and subsequent HF hospitalizations•Time to composite all-cause mortality or HF hospitalization•Time to all-cause mortality•Safety and tolerabilityExploratory endpoints: •Time to first occurrence of composite HF hospitalization or urgent HF visits; first CV hospitalization•Number of HF hospitalizations•Change in QoL (KCCQ and EQ-5D) Randomized, double blind 1:1 ACC March 2020 VICTORIA: 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%•Guideline based HF therapies•eGFR > 15 •Recent HFH or IV diuretic use•With very elevated natriuretic peptides (BNP or NT-proBNP) No run-in BNP ≥ 300 & pro-BNP ≥ 1000 pg/ml NSRBNP ≥ 500 & pro-BNP ≥ 1600pg/ml AF VICTORIA: Baseline CharacteristicsVericiguat (N=2526) Placebo (N=2524)Age mean (SD)67.5 (12.2)67.2 (12.2)Female sex 605 (24.0%)603 (23.9%)Index event at RandomizationHF hospitalization < 3 mos 1673 (66.2%)1705 (67.6%)HF hospitalization 3 to 6 mos 454 (18.0%)417 (16.5%)IV diuretic for HF < 3 mos(no hospitalization)399 (15.8%)402 (15.9%)EF % (SD) 29.0 (8.3)28.8 (8.3)NYHA classIII–IV baseline, 1045 (41.4%)1024 (40.6%)NT-proBNPMedian (25th–75th) pg/mL 2804 (1572-5380)2821(1548 –5206)Triple guide-based therapy* 1480 (58.7%)1529 (60.7%)ICD,BV pacemaker(or both) *813 (32.2%)802 (31.8%) * For vericiguat/ placebo %’s are of n’s 2521 & 2519 Primary Endpoint: CVD/HFHHR 0.90 (95% CI 0.82–0.98)P-value 0.019 Absolute event reduction 4.2 / 100 pt-yrs Secondary EndpointsHR 0.93 (95% CI 0.81–1.06)P-value 0.269 HR 0.90 (95% CI 0.81–1.00)P-value 0.048 First HF HospitalizationCVD •Symptomatic hypotension + syncope more common w/ vericiguat•More anemia developed with vericiguat (7.6%) than placebo (5.7%)•SAE were similar: vericiguat (32.8%), placebo (34.8%)•No effects of vericiguaton either electrolytes or renal function•At 12 months, 10 mg target dose achieved: vericiguat (89.2%), placebo (91.4%) Safety & Tolerability •Vericiguatwas significantly more effective than placebo in reducing:–The composite endpoint of CV death or HF hospitalization (primary endpoint)–HF hospitalization (first and recurrent)•There was directionally aligned reduction in CV death•No significant change in all-cause mortality•Vericiguatgenerally safe and well tolerated•There was excellent guideline-based HF therapy and patient follow-up VICTORIA Summary thecvc.ca/VICTORIA PARADIGM-HFDAPA HFVICTORIAComparatorSacubitril/ValsartanComparatorDapagliflozinComparatorVericiguatPrimary Endpoint*13.210.515.611.637.833.6Absolute Rate Reduction2.74.04.2CV Death*7.56.07.96.513.912.9Absolute Rate Reduction1.51.41.0First HF Hospitalization*NANA9.86.929.125.9Absolute Rate Reduction1.62.93.2 VICTORIA in Context Butler et al. Circulation*Rates expressed / 100 patient years OmecamtivmecarbilGALACTIC-HF •Mitotropesvs. Calcitropesvs. Myotropes•OME: –Direct cardiac myosin activator–duration of systole by overall # of active cross-bridges–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. Myo/ Mitotropesare where its at Calcitropes= bad Mitotropes= maybe Myotropes= maybe 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 AHA 2020 •65 year old, 79% male•EF 27%•NT-proBNP1998 pg/ml•eGFR 59 GALACTIC Baseline SGLTi 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 ≥30 mL/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 ≥20 mL/min/1.73 m2•Diabetes and no diabetes •Patients with NYHA class II-IV heart failure with ANY EF and elevated NT-proBNP•eGFR ≥30 mL/min/1.73 m2•Diabetes onlySample 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% ESC 2020Cancelled DAPA-HF and NT-proBNP ACC 2020 IV Iron 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) *Canada sites VICTORIA: vericiguata win for patients EF < 45%, eGFR > 15GALACTIC: coming soonDAPA-HF: Confirms NT-proBNPreduction with dapagliflozin The future is often invertedVericiguat(now)Omecamtiv(maybe)Dapagliflozin (now) Heart Failure Update Trainee Research Competition WinnerDavid BobrowskiUniversity of TorontoStatins Are Associated with Lower Risk of Heart Failure After Anthracycline and Trastuzumab Chemotherapy for Early Stage Breast CancerFinalistJustin ChowMcMaster UniversityPulmonary Artery Catheterization in Cardiogenic Shock: A Systematic Review and Meta-Analysis Image not available. FinalistPatrick Prud’hommeUniversité de SherbrookeHigh Sensitivity Troponin T and Nt-pro-BNP Prognostic Value in Predicting Cardiovascular Outcomes in Patients Undergoing Chronic HemodialysisFinalistFelicia TaiUniversity of TorontoPrognosis of heart failure following cardiotoxic breast cancer chemotherapy: a retrospective population-based matched cohort study