solomon. expanding use of arnis
TRANSCRIPT
ExpandingtheroleofARNIsinHeartFailure
ScottD.Solomon,MD
TheEdwardD.FrohlichDistinguishedChair
ProfessorofMedicine,HarvardMedicalSchool
BrighamandWomen’sHospital
DISCLOSURES
• Dr.SolomonhasreceivedresearchgrantsfromAlnylam,Amgen,AstraZeneca,Bellerophon,Bayer,BMS,Celladon,Cytokinetics,Eidos,Gilead,GSK,Ionis,LoneStarHeart,Mesoblast,MyoKardia,NIH/NHLBI,Neurotronik,Novartis,Respicardia,SanofiPasteur,Theracos,andhasconsultedforAkros,Alnylam,Amgen,Arena,AstraZeneca,Bayer,BMS,Cardior,Cardurion,Corvia,Cytokinetics,Daiichi-Sankyo,Gilead,GSK,Ironwood,Merck,Myokardia,Novartis,Roche,Takeda,Theracos,QuantumGenetics,Cardurion,AoBiome,Janssen,CardiacDimensions,Tenaya,Sanofi-Pasteur,Dinaqor,Tremeau,CellProThera,Moderna,AmericanRegent
TheMostAppropriateTermforHeartFailurewithLVEF>40%is:1. HeartFailurewithPreservedEjectionFraction2. DiastolicHeartFailure3. HeartFailurewithNormalEjectionFraction4. HeartFailurewithmildlyreducedandPreserved
EjectionFraction5. HeartFailurewithMidly ReducedandNormal
EjectionFraction6. Noneoftheabove
The Ejection Fraction “Spectrum” of Heart Failure
HFrEF HFpEF
Similar Signs and Symptoms to HFrEF
HFpEF is increasing in Prevalence
Chang P. Circulation 2018
GlobalVariationInHFpEF:PARAGON.
Tromp,etal.CircHeart Fail2021
• ConsiderAlternativeDiagnoses• SymptomaticTreatmentwithDiuretics• TreatmentofHypertension• TreatmentofotherComorbidities• RatecontrolinAtrialFibrillation(?MaintainSR)• DiagnoseandTreatIschemia
SomepatientswithHFpEFmayhaveother(treatable)diseasesHypertrophiccardiomyopathy,amyloidheartdisease,otherinfiltrativediseases
• HFpEFisheterogeneouswithmultiplecauses
• Prospectivelyscreened consecutivepatients ≥60yearsoldadmittedduetoHFpEFwithLVhypertrophy(≥12mm).
• 120HFpEFpatients(59%women,82+8years).TTRgene,andnomutationswerefound.
• diphosphono-1,2-propanodicarboxylicacid(99mTc-DPD)scintigraphy
HypertrophicCardiomyopathy• Unexplainedventricularhypertrophy
• Myocytedisarray
• Causedpredominantly bysarcomeric mutations
• CanpresentwithHFpEFandwhenhypertrophy isnotovert,canbedifficult todistinguish
FromHeartDisease,11th Edition
DiureticUseinHFpEF
• Ifthereisnoneedfordiuretics,thisisprobablynotheartfailure!
• DiureticuseinHFpEF isempiric– butappearstoworktoreducecongestion.
• Loopandthyazide diureticsarereasonable
TreatmentofHypertensionPREVENTSHeartFailure
Upadhya … Kitzman D. et al. Spring Investigators. Circ Heart Fail 2017
AtrialFibrillationportendsincreasedriskinHFpEF
CVDeathorHFHospitalization
Cikes M.etal.JACC-HF2018
0-90 days 90 days to 1 Year > 1 YearHa
zard
for P
rimar
y Ou
tcom
e
0.00
0.10
0.20
0.30
0.40
0.50
Probability
0 12 24 36 48 60 72Months
HR=0.82 (0.69-0.98)
HR=1.10 (0.79-1.51)
Interaction p=0.122
US, Canada, Argentina, Brazil
Russia, Rep Georgia
Placebo:280/881 (31.8%)
Placebo:71/842 (8.4%)
TOPCAT:ResultsbyRegion
Pfeffer MA et al. Circulation. 2015 Jan 6;131(1):34-42
AT1 receptor
Angiotensinogen(liversecretion)
Angiotensin I
AngiotensinII
NH
N
NN
N
O
OH
O
Valsartan
OH
ONH
OOH
O
ReninAngiotensinSystem
VasoactivePeptideSystem
Vasodilation� bloodpressure� sympathetictone�aldosterone levels� fibrosis� hypertrophyNatriuresis/Diuresis
Inactive fragments
XNeprilysin
Vasoconstriction� bloodpressure� sympathetictone� aldosterone� fibrosis� hypertrophy
X
Heart Failure
Sacubitril/Valsartanpro-BNP
NT-proBNP
ANP BNP CNPAdrenomedullinBradykininSubstanceP(angiotensinII)
Sacubitril↓
Sacubitrilat
LCZ696isanovelcrystallinecomplexconsistingofthemolecularmoietiesof
valsartanandsacubitril inanequimolar ratio
Sacubitril/Valsartan– Afirst-in-classAngiotensinReceptorNeprilysin Inhibitor– SimultaneouslyInhibitsNEPandtheRAS
Vardeny O.JACC-HF2014
PARAGON-HFprimaryresultsRecurrenteventanalysisoftotalHFhospitalizations and CVdeath*
*SemiparametricLWYYmethod.
0
5
10
15
20
25
30
35
40
45
50
55
Meancumulativeeven
tsper100patients
0 1 2 3 4Years
TotalHFhospitalizationsandCVdeath
Valsartan(n=2389)1009events,14.6per100pt-years
Sacubitril/valsartan(n=2407)894events,12.8per100pt-years
Rateratio0.87(95%CI0.75,1.01)p=0.059
Solomon etal.NEJM2019
ImprovementinNYHAFunctionalClassandKCCQCSSwithSacubitril/Valsartan
Sac/Val ValsartanEffect Size
(95% CI)P-value(2-sided)
NYHAclassfavorablechangeat8months– n 2316 2302
ImprovedUnchangedWorsened*
15.0%76.3%8.7%
12.6%77.9%9.6%
OR, 1.45 (1.13 – 1.86) 0.004
KCCQ clinical summary score at 8 months – n 2250 2226
LSMofchange frombaseline (SE) -1.5 (0.4) -2.5 (0.4) Difference, 1.0 (0.0 – 2.1) 0.051
≥5 point Improvement 33.0% 29.6% 0.019
≥5 point Deterioration 33.5% 34.5% 0.467
Improvement in Worsening Renal Function with Sacubitril ValsartanSacubitril/Valsartan Reduced the Risk of the Composite Renal Endpoint
Composite
Sacubitril/ValsartanN=2407n (%)
ValsartanN=2389n (%)
Compositerenalendpoint 33(1.4)
64(2.7)
(i)Renal death 1 1
(ii)ReachingESRD 7 12
(iii) ≥50%declineineGFRrelativetobaseline
27 60
0.10
0.00
0.02
0.04
0.06
0.08
0 1 2 3 4
23892407
22732320
21452195
10331049
135129
Number at Risk
valsartansacubitril/valsartan
Prop
ortio
n of
Pat
ient
s
Years
HR0.50(95%Cl0.33– 0.77),p=0.001
valsartansacubritril/valsartan
SignificantHeterogeneityinMultivariateAnalysisbyEjectionFractionandSex
Subgroup
OverallAge (years) Less than 65 years 65 years or olderAge (years) Less than 75 years 75 years or olderGender Male FemaleRace Caucasian Black Asian OtherRegion North America Latin America Western Europe Central Europe Asia/PacificDiabetic Yes NoLVEF at or below median (57%) above median (57%)History of AF Yes NoScreening NT−proBNP at or below median (911pg/mL) above median (911pg/mL)Screening SBP at or below median (137mmHg) above median (137mmHg)MRA use Yes NoBaseline eGFR <60 mL/min/1.73m2 >=60 mL/min/1.73m2NYHA class I/II III/IV
No. ofEvents/Patients
1903/4796
276/8251627/3971
938/2597965/2199
980/2317923/2479
1542/390789/102
237/60735/180
478/55983/370
544/1390466/1715332/762
1041/2069862/2727
1048/2495855/2301
1140/2521763/2275
708/23791183/2378
984/2450919/2344
543/12381360/3558
1115/2341787/2454
1402/3843499/951
Hazard Ratio(95% CI)
0.87 (0.75−1.01)
0.99 (0.64−1.53)0.85 (0.73−0.99)
0.82 (0.66−1.02)0.92 (0.76−1.11)
1.03 (0.85−1.25)0.73 (0.59−0.90)
0.83 (0.71−0.97)0.69 (0.24−1.99)1.25 (0.87−1.79)1.03 (0.47−2.28)
0.80 (0.57−1.14)1.33 (0.75−2.36)0.69 (0.53−0.89)0.97 (0.76−1.24)1.10 (0.79−1.52)
0.89 (0.74−1.09)0.84 (0.68−1.04)
0.78 (0.64−0.95)1.00 (0.81−1.23)
0.83 (0.69−1.00)0.94 (0.75−1.18)
0.85 (0.67−1.08)0.87 (0.73−1.05)
0.88 (0.72−1.07)0.86 (0.69−1.06)
0.73 (0.56−0.94)0.94 (0.79−1.12)
0.79 (0.66−0.95)1.01 (0.80−1.27)
0.90 (0.76−1.06)0.79 (0.59−1.06)
0.4 0.6 0.8 1.0 2.0
Rate Ratio (95% CI)
Subgroup
OverallAge (years) Less than 65 years 65 years or olderAge (years) Less than 75 years 75 years or olderGender Male FemaleRace Caucasian Black Asian OtherRegion North America Latin America Western Europe Central Europe Asia/PacificDiabetic Yes NoLVEF at or below median (57%) above median (57%)History of AF Yes NoScreening NT−proBNP at or below median (911pg/mL) above median (911pg/mL)Screening SBP at or below median (137mmHg) above median (137mmHg)MRA use Yes NoBaseline eGFR <60 mL/min/1.73m2 >=60 mL/min/1.73m2NYHA class I/II III/IV
No. ofEvents/Patients
1903/4796
276/8251627/3971
938/2597965/2199
980/2317923/2479
1542/390789/102
237/60735/180
478/55983/370
544/1390466/1715332/762
1041/2069862/2727
1048/2495855/2301
1140/2521763/2275
708/23791183/2378
984/2450919/2344
543/12381360/3558
1115/2341787/2454
1402/3843499/951
Hazard Ratio(95% CI)
0.87 (0.75−1.01)
0.99 (0.64−1.53)0.85 (0.73−0.99)
0.82 (0.66−1.02)0.92 (0.76−1.11)
1.03 (0.85−1.25)0.73 (0.59−0.90)
0.83 (0.71−0.97)0.69 (0.24−1.99)1.25 (0.87−1.79)1.03 (0.47−2.28)
0.80 (0.57−1.14)1.33 (0.75−2.36)0.69 (0.53−0.89)0.97 (0.76−1.24)1.10 (0.79−1.52)
0.89 (0.74−1.09)0.84 (0.68−1.04)
0.78 (0.64−0.95)1.00 (0.81−1.23)
0.83 (0.69−1.00)0.94 (0.75−1.18)
0.85 (0.67−1.08)0.87 (0.73−1.05)
0.88 (0.72−1.07)0.86 (0.69−1.06)
0.73 (0.56−0.94)0.94 (0.79−1.12)
0.79 (0.66−0.95)1.01 (0.80−1.27)
0.90 (0.76−1.06)0.79 (0.59−1.06)
0.4 0.6 0.8 1.0 2.0
Rate Ratio (95% CI)
Subgroup
OverallAge (years) Less than 65 years 65 years or olderAge (years) Less than 75 years 75 years or olderGender Male FemaleRace Caucasian Black Asian OtherRegion North America Latin America Western Europe Central Europe Asia/PacificDiabetic Yes NoLVEF at or below median (57%) above median (57%)History of AF Yes NoScreening NT−proBNP at or below median (911pg/mL) above median (911pg/mL)Screening SBP at or below median (137mmHg) above median (137mmHg)MRA use Yes NoBaseline eGFR <60 mL/min/1.73m2 >=60 mL/min/1.73m2NYHA class I/II III/IV
No. ofEvents/Patients
1903/4796
276/8251627/3971
938/2597965/2199
980/2317923/2479
1542/390789/102
237/60735/180
478/55983/370
544/1390466/1715332/762
1041/2069862/2727
1048/2495855/2301
1140/2521763/2275
708/23791183/2378
984/2450919/2344
543/12381360/3558
1115/2341787/2454
1402/3843499/951
Hazard Ratio(95% CI)
0.87 (0.75−1.01)
0.99 (0.64−1.53)0.85 (0.73−0.99)
0.82 (0.66−1.02)0.92 (0.76−1.11)
1.03 (0.85−1.25)0.73 (0.59−0.90)
0.83 (0.71−0.97)0.69 (0.24−1.99)1.25 (0.87−1.79)1.03 (0.47−2.28)
0.80 (0.57−1.14)1.33 (0.75−2.36)0.69 (0.53−0.89)0.97 (0.76−1.24)1.10 (0.79−1.52)
0.89 (0.74−1.09)0.84 (0.68−1.04)
0.78 (0.64−0.95)1.00 (0.81−1.23)
0.83 (0.69−1.00)0.94 (0.75−1.18)
0.85 (0.67−1.08)0.87 (0.73−1.05)
0.88 (0.72−1.07)0.86 (0.69−1.06)
0.73 (0.56−0.94)0.94 (0.79−1.12)
0.79 (0.66−0.95)1.01 (0.80−1.27)
0.90 (0.76−1.06)0.79 (0.59−1.06)
0.4 0.6 0.8 1.0 2.0
Rate Ratio (95% CI)
Primaryendpoint
Male 980/2317 1.03(0.85–1.25)
0.73(0.59–0.90)
Sex
Female 923/2479
atorbelowmedian(57%) 1048/2495 0.78(0.64–0.95)
1.00(0.81–1.23)
LVEF
abovemedian(57%) 855/2301
Rateratio(95%CI)0.4 0.6 0.8 1.0 2.0
P=0.002(continuous)
P=0.03(categorical)
P<0.006
Multivariableinteractionp-value
Rateratio(95%CI)
No.ofevents/patients
Subgroup
Onlyinteractionsforsexandejectionfractionremainednominallysignificant
Solomon etal.NEJM2019
SubgroupNo.of
Events/PatientsRateRatio(95%CI)
OverallEF 1903/4796 0.87(0.75–1.01)
≤50 512/1208 0.82(0.63–1.06)
>50–57 536/1287 0.77(0.57–1.03)>57–63 467/1202 0.91(0.68–1.22)>63 388/1099 1.09(0.80–1.47)
Treatment Effect by Ejection Fraction QuartilesPrimary Composite Total HF Hospitalizations and CV Death
Subgroup estimates are based on re-running the primary analysis model for each of the four subgroups defined by the by LVEF quartiles.
0.4 1.610.6 0.8 1.2 1.4
Sacubitril/Valsartan Compared to RAS inhibitorPre-specified Pooling of PARAGON-HF and PARADIGM-HF (N=13,195)
0.003
P-value
< 0.001
< 0.001
<<Solomon et al. Circulation. 2020;141:352–361>><<Solomon et al. AHA 2019>>
(hazard ratio)
(rate ratio)
(rate ratio)
P-value
(hazard ratio)
<0.001
<0.001
<0.001
(hazard ratio)
(hazard ratio)
Treatment Effect by Continuous Ejection FractionTotal HF Hospitalizations and CV Death (PARAGON-HF Primary Endpoint)
Rate ratio = 1 (unity)
95% CI
Sac/val better
RASi better
95% CI
P-interaction=0.02
Solomon etal.AHA2019;Circulation2019
Treatment Effect by LVEF and SexBenefit extends to higher LVEF in Women
Total HF Hospitalizations and CV Death
Men
Women
Solomon etal.AHA2019;Circulation2019
7,599 patients with NYHA class II-IV heart failure and no LVEF exclusion
FemaleMale
LVEFinMenandWomenwithHeartFailureLVEF distribution in CHARM
<<McMurray JJV, Jackson AM et al Circulation. 2020;141:338–351>>
WeCANtreatthemid-rangeofheartfailure!
Lund…Solomon.CHARMInvest.EurJHeartFail
.51
1.5
22.
5
Trea
tmen
t Effe
ct (H
azar
d R
atio
)
40 50 60 70 80Ejection Fraction (%)
.51
1.5
22.
5
Trea
tmen
t Effe
ct (H
azar
d R
atio
)
40 50 60 70 80Ejection Fraction (%)
.51
1.5
22.
5
Trea
tmen
t Effe
ct (H
azar
d R
atio
)
40 50 60 70 80Ejection Fraction (%)
.51
1.5
22.
5
Trea
tmen
t Effe
ct (H
azar
d R
atio
)
40 50 60 70 80Ejection Fraction (%)
SolomonSDetal.EurHeartJ.2015
CHARM
TOPCAT
PARADIGM-PARAGON
CV death or HF hospitalizations (time-to-first)
Treatment Effect by LVEF: 3 Different Therapies
<<Dewan P et al Eur J Heart Fail 2020;22: 898-901>>
CV death or HF hospitalizations (time-to-first)
Treatment Effect by LVEF and SexBenefit Extends to Higher LVEF in Women
<<Dewan et al. Eur J Heart Fail 2020; 22:898-901>>
Estimated Absolute Benefit: Potential Events Prevented by Treating 1000 Patients for 3 Years
*Calculations are based on the between treatment group differences in exposure-adjusted event rates
Primary composite events
Prevented*
HF hospitalizations
prevented*
PARADIGM-HF 122 76
PARAGON-HF: Overall 54 49
PARAGON-HF: LVEF ≤median 108 106
If there really is an effect in patients with a LVEF≤57%, it may be substantial
FDAAdvisoryCommitteeandApprovalofExpandedIndicationforSacubitril/valsartan• OnDecember15,2020anFDAadvisorycommitteevoted12-1toapproveanexpandedindicationforsacubitril/valsartanbasedonthePARAGON-HFResults,andonFebruary16,2021FDAapprovedanexpandedindicationforsacubitril/valsartan:
Sacubitril/valsartanisindicatedtoreducetheriskofcardiovasculardeathandhospitalizationforheartfailureinadultpatientswithchronicheartfailure.Benefitsaremostclearlyevidentinpatientswithleftventricularejectionfraction(LVEF)belownormal.LVEFisavariablemeasure,souseclinicaljudgmentindecidingwhomtotreat[seeClinicalStudies(14)].
EstimatingAbsoluteRiskReductionsandNNTinPARAGON-HFwith3YearsofTreatment
1)IdentifyPotentiallyEligiblePatientswith
HFintheUS
2)ApplyVariousLVEFCriteria toDefine“BelowNormal”
3)EstimateNNTwith3YearsofTreatment
ForecastPotential ImpactonWorseningHFEventswithFull
Implementation
LVEF≤60%(n=3,371)
LVEF≤57%(n=2,495)
LVEF≤55%(n=2,206)
LVEF≤50%(n=1,208)
TotalHFHosp 12 9 8 10CVDeath+TotalHF
Hosp 10 9 8 10
CVDeath+TotalHFEvents(Hosp+UrgentVisits)
10 9 7 9
ApplyingSex-SpecificLVEFRangestoPARAGON-HF:MenNNTRange:27-34WomenNNT:5
Vaduganathan M….Solomon SDESC-HF2021;JAMACardiol InPress
84
Filtered glucose load >180 g/day
SGLT1compensate
SGLT2~90%
SGLT2 inhibitors reduce glucose reabsorption
in the proximal tubule, leading to
urinary glucose excretion* and
osmotic diuresis
SGLT2inhibitor
DM: ~70-80 g glucose/dayNon-DM: ~50 g glucose/day
SodiumExcretion
Volume Loss
Glucose Excretion
SGLT: sodium glucose cotransporter, DM: diabetes mellitus*Loss of ~80 g of glucose per day = 240 cal/day1. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.
Slide courtesy of Faiez Zannad
05
1015
2025
3035
Cum
ulat
ive
Perc
enta
ge(%
)
2371 2258 2163 2075 1917 1478 1096 593 210Placebo2373 2305 2221 2147 2002 1560 1146 612 210Dapagliflozin
Number at Risk
0 3 6 9 12 15 18 21 24Months since Randomization
Placebo
DAPA-HFHR 0.74 (0.65, 0.85)p=0.00001
Reduction in CV Death/HF hospitalization/Urgent HF visit in Heart Failure with Reduced Ejection Fraction
NNT=21
Dapagliflozin
SGLT-2inhibitors:DevelopedfordiabetesbutprovingbeneficialinHeartFailure
Improved Outcomes in Patients with Diabetes and HFpEF in two SGLT-2 Trials
0 6 12Months Since Randomization
18 24
20
0
40
60
80
100Ev
ents
Per
100
Patie
nts
HR 0.63 (95% CI 0.45-0.89), P=0.009 ARR: 11.6 Events Per 100 Patient-Years Treatment Patient-Years to Avoid 1 Event: 9
Placebo
Sotagliflozin
59.0
37.5
Bhatt DL, Szarek M, Pitt B, et al., and Steg PG. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
OngoingHFpEF TrialsDELIVER Study Design Overview
35
Dapagliflozin 10 mgSoC
PlaceboSoC
E R
Visit 1 2 3 4 5 6 7
Day 240 48030 1201-21 360
PACD SCV
≤6 weeks
E=Enrolment; R=Randomization; SoC= Standard of Care; PACD=Primary Analysis Censoring Date; SCV=Study Closure Visit; LVH= Left Ventricular Hypertrophy; LAE= Left Atrial Enlargement
Months 8 161 4 12
8
600
20
ü Heart failure (NYHA class II-IV)
ü Typical symptoms/signs for HF for ≥6 weeks
ü Requiring treatment with diuretic(s) for HF
ü LVEF >40% AND evidence of structural heart disease (LVH or LAE)
ü Elevated NT-pro BNP
ü Ambulatory OR Hospitalized (off intravenous heart failure therapy)
ü No iv diuretics within 24 hours prior to randomization
Primary endpointTime to first adjudicated event of either:• CV death • Hospitalization for HF• urgent HF visit
4700 randomized patients
ClinicalTrials.gov NCT03619213
8"mmLA
RA8 mm
Feldman T…Shah SJ. Circ Heart Fail 2016
8"mmLA
RA
IASD proposed mode of action: dynamic decompression of overloaded LA chamber by shunting blood from LA à RA
47
Potassium > 5.0 mmol/L; eGFR <25 mL/min/1.73 m²
Continuous MRA use (>3 months) in the 12m prior to enrollment; MRA use in the 30d prior to randomization
MI or PCI 30d prior to randomization
Cardiogenic shock at randomization, prior to first intake of study drug
History of dilated cardiomyopathy, peripartum cardiomyopathy, chemotherapy induced cardiomyopathy, or infiltrative cardiomyopathy. Amyloidosis.
Alternative causes for symptoms: severe lung disease, anemia with hemoglobin < 10g/dL, valve disease, primary PH, BMI >50 kg/m2K
ey E
xclu
sion
Crit
eria
Symptomatic HF (NYHA II-IV) with documented EF ≥ 40% within the last 12 months, ambulatory or with prior heart failure hospitalization < 3m (enrollment prior to hospital discharge is encouraged)
NT-proBNP ≥ 300 pg/mL in sinus rhythm (or ≥ 900 pg/mL in atrial fibrillation) at following timepoints:
within 90 days prior to randomization if patient had been hospitalized for HF requiring initiation or change in HF therapy OR if patient had an urgent visit for HF requiring IV diuretic therapy
within 30 days prior to randomization if patient has not been hospitalized for HF in the past 3m
Structural heart disease associated with HFpEF: left atrial enlargement or left ventricular hypertrophy on any local measurement within the last 12 months
Treatment with diuretics in the 30d prior to randomization
Key
Incl
usio
n C
riter
ia
Visits: Month 1, then 3-monthly for first 12 months, 4-monthly visits thereafter with telephone contact in between
1:1Randomization
Finerenone 10, 20 and 40 mg based on eGFR: ≤60 max dose 20 mg, >60, max. 40 mg
Matching Placebo
• N = 5,500 randomized; Recruitment period 24 months, treatment up to 42 months
Primary EndpointComposite of CV death and total / recurrent HF events (hospitalization/urgent visit)
Secondary EndpointsChange in TSS of KCCQTime to first renal composite endpointTime to all-cause mortality
Exploratory Endpoints
Stud
y En
dpoi
nts
Steering Committee: S. Solomon (Chair), J. McMurray (Co-Chair), Carolyn Lam, Sanjiv Shah, Faiez Zannad, Bertram Pitt, Adriaan Voors
Summary
Therapyforheartfailurewithmildlyreducedandpreservedejectionfractionhasbeenempiric
Importanttoruleoutother,targetable,causesofdisease
Therapiesthathavebeenbeneficialinpatientswithheartfailureandreducedejectionfractionarelikelybeneficialinpatientswithheartfailureandmildlyreducedejectionfraction
Severaladditionaltherapiesarebeingtested…staytuned!