Trials

Question 1

CONSENSUS

Answer 1

NEJM 1987
RCT, enalapril (vs placebo) improved survival
-in >250 pts w/ NYHA IV HFrEF 6mo and 12 mo

Question 2

SOLVD

Answer 2

NEJM 1992

• RCT, enalapril (vs placebo) reduced HF hospitalizations, HF incidence and mortality
• in > 4200 asymptomatic HF patient w/ EF < 35% taking diuretics/digoxin after 4 years

Question 3

CHARM-added

Answer 3

Lancet 2003

-Addition of candesartan (vs placebo) to ACEi in HFrEF, EF < 40%, reduced CV mortality and HF hospitalization

Question 4

CHARM-alternative

Answer 4

Lancet 2003

• Candesartan (vs placebo) reduced CV mortality (by 20%) and HF hospitalizations (by 40%)
• in >2000 pts with HFrEF, who were intolerant to ACEi

Question 5

I-PRESERVE

Answer 5

NEJM 2008

-irbesartan did NOT reduced death or hospitalization, in pts w/ HFrEF, EF<45%

Question 6

PARADIGM-HF

Answer 6

NEJM 2014

• ARNI (vs enalapril 10 mg BID) reduced CV mortality, all-cause mortality, and HF hospitalization
• in > 8000 chronic HFrEF pts, EF < 40% and < 35%, NYHA II-IV.
• ARNI was well tolerated except for hypotension.

Question 7

PIONEER-HF

Answer 7

NEJM 2019

• ARNI (vs enalapril 10 mg BID) reduced NT-proBNP concentration
• in > 800 pts w/ acute decompensated HF, at 4 and 8 weeks.

Question 8

EVALUATE-HF

Answer 8

JAMA 2019

• ARNI at target dose 97/103 mg BID (vs enalapril 10 mg QD) did not show differences in change of aortic stiffness (measured with characteristic impedance via echo)
• neither of them lowered aortic stiffness
• in HFrEF < 40%, after 12 weeks

Question 9

PARAGON-HF

Answer 9

NEJM 2019

• ARNI 97/103 mg BID (vs valsartan 160 mg BID) did NOT reduce HF hospitalizations/CVD death (rate ratio 0.87, 95%CI 0.75-1.01)
• in > 4800 pts w HFpEF > 45%, NYHA II,III,IV, structural heart disease
• However, ARNI was a/w less renal dysfunction (1.4% vs 2.7%, HR 0.5)
• PARAGON was performed given positive results of PARAMOUNT (phase 2 trial in HFpEF).
• FDA approved ARNI in HFpEF in Dec 2020 after analyzing PARAGON-HF

Question 10

OVERTURE

Answer 10

• omapatrilat (a previous neprilysin inhibitor) is a/w higher freq of angioedema (OVERTURE trial).
• Omapatrilat was a/w lower mortality and hospitalization as compared to enalapril, but produced too much angioedema!

Question 11

MERIT-HF

Answer 11

Lancet 1999

• metoprolol succinate 12.5-25 mg daily (vs placebo) reduced all-cause mortality (by 34%), all-cause hospitalizations, and CV events
• in ~4000 pts w/HFrEF <40%, NYHA II-III

Question 12

CIBIS-II

Answer 12

Lancet 1999

• bisoprolol (start dose 1.2510 mg daily (vs placebo) reduced all-cause mortality
• in HFrEF < 35%, NYHA III-IV

Question 13

COPERNICUS

Answer 13

Circulation 2002

• carvedilol (3.125 – 25 mg BID, uptitrated q2w) vs placebo reduced risk of death and HF hospitalizations (by 31%)
• in > 2000 euvolemic pts w/HFrEF < 25%, NYHA III-IV

Question 14

COMET

Answer 14

Lancet 2003

• carvedilol 3.125-25 mg BID (vs metoprolol tartrate 5-50 mg BID) reduced all-cause mortality
• in >3000 pts w/ HFrEF < 35%, NYHA II-IV
• after 4.8 years
• Largest and most well-known head-to-head trial of Beta blockers
• Criticism: it used metoprolol Tartrate (instead of succinate).

Question 15

RALES

Answer 15

NEJM 1999

• spironolactone 25-50 mg daily (vs placebo) reduced all-cause mortality (by 30%), SCD, and HF hospitalization
• > 1600 in pts w/ HFrEF < 35%, NYHA III-IV
• Aldactone a/w gynecomastia/mastalgia (10% vs 1%).
• Only 10% of pts were on beta blockers

Question 16

EPHESUS

Answer 16

NEJM 2003

• eplerenone 25-50 mg daily (vs placebo) reduced mortality in patients with acute MI (3-14 d) complicated by LV dysfunction (EF < 40%) and HF.
• A lot more patients (than in RALES) were on beta blockers.

Question 17

EMPHASIS-HF

Answer 17

NEJM 2011

• eplerenone (vs placebo) reduced risk of death (by 15%) and hospitalization
• in > 2700 pts with HFrEF <30%, NYHA II.
• 85% were on beta blockers (only 10% in RALES).

Question 18

TOPCAT

Answer 18

NEJM 2014

• spironolactone 15-45 mg daily (vs placebo) did not reduce CV mortality, HF hospitalizations, of aborted cardiac arrests
• in ~ 3400 pts w/ s/s HF with LVEF > 45%, as compared to placebo.
• There was a small reduction of HF hospitalizations: lead to subanalysis in 2017: Eastern European (Russian/Georgian) vs North/South American subjects  Eastern European subjects likely were not taking medication (metabolites were undetectable, potassium did not vary).
• Criticism: used broad ACC/AHA HfpEF definitions, so maybe included pts who had no HF and did not need med.

Question 19

V-HeFT

Answer 19

NEJM 1986

• ISDN/hydralazine (vs prazosin and vs placebo) improved survival in >600 patients with HFrEF, EF<45%.
• A subgroup analysis showed statistically significant benefit among self-identified black patients.

Question 20

V-HeFT II

Answer 20

NEJM 1991

• enalapril improved survival compared to ISDN/hydralazine
• in > 800 male pts w/HFrEF, EF<45%, already taking diuretics and digoxin.

Question 21

A-HeFT

Answer 21

NEJM 2004

• ISDN/hydralazine (vs placebo) improved survival (40%) and hospitalization
• in > 1000 blacks with HFrEF on ACEi/ARB/BB/diuretics

Question 22

DAPA-HF

Answer 22

NEJM 2019

• RCT, dapagliflozin (10 mg QD) (vs placebo) +GDMT was a/w less CVD death/HF exacerbation (HR 0.7, 16.3% vs 21.2%) and all-cause mortality
• after 18.2 months, in > 4700 pts with NYHA II-VI HFrEF < 40%, regardless of diabetes status.

Question 23

EMPEROR-Reduced

Answer 23

NEJM 2020

• empagliflozin 10mg/d (vs placebo) +GDMT was a/w less CV death/ HF hospitalization (HR 0.75, 19.4 vs 24.7%), slower eGFR decline, and worse renal outcomes
• in > 3700 pts w class II-IV HFrEF < 40%, regardless of diabetes status

Question 24

SUGAR-DM-HF

Answer 24

Circulation 2021

• empagliflozin 10mg/d (vs placebo) +GDMT was a/w reduced LV end-systolic volume index by 6.0, reduced LV end-diastolic volume index by 8.2, no difference in global longitudinal strain (CMR), reduced N-terminal pro-BNP by 28%, no difference in KCCQ, 6MWT, or B-lines
• in pts w NYHA II-IV HFrEF < 40% + T2DM or prediabetes

Question 25

DIG

Answer 25

NEJM 1997 - digoxin (vs placebo) reduced hospitalizations (by 28%) but not mortality - in > 6000 pts w/HFrEF <45%

Question 26

SHIFT

Answer 26

Lancet 2010 - ivabradine (vs placebo) reduced HF mortality and hospitalizations - in > 6000 pts with HFrEF < 35%, NYHA II-IV, w/ HF hospitalization in the preceding year, and resting HR>70 despite being on max-tolerated GDMT

Question 27

VICTORIA

Answer 27

NEJM 2020 - vericiguat (target dose 10mg QD), as compared to placebo, was a/w lower death from CV causes (16.4% vs 17.5%) or HF hospitalization (HR 0.9, CI 0.8-1.0). - over 10.8 mo, among pts with high-risk HF (NYHA II-IV, EF <45%), - Vericiguat was a/w symptomatic hypotension in 9.1% (7.9% in placebo), and syncope.

Question 28

AFFIRM-HF

Answer 28

Lancet 2020 - IV iron (ferric carboxymaltose, for up to 24 weeks) vs placebo reduced risk of HF hospitalizations without difference in CV death - in > 1100 pts w iron deficiency (ferritin < 100, transferrin sat < 20%) and LVEF > 50% stabilized after episode of ADHF

Question 29

ESCAPE

Answer 29

JAMA 2005 - pulmonary artery catheter-guided therapy did not improve survival and increased adverse events, compared to clinical assessment-guided therapy - in >400 patients with ADHF (EF < 30%)

Question 30

PAC-MAN

Answer 30

Lancet 2005 -in critically-ill patients, pul artery catheter did not show benefit or harm, vs no catheter. RCT.

Question 31

EVEREST

Answer 31

JAMA 2007 - tolvaptan PO (vs placebo) did not reduce all-cause mortality, CVD mortality, of HF rehospitalization - in > 4000 patients with acute HF exacerbation, for 60 days

Question 32

DOSE

Answer 32

NEJM 2011 - high-dose (2.5 x home dose) loop diuretics (vs home dose) was a/w better symptom improvement, while diuretic infusion is not better than intermitted diuretic boluses (but were less likely to require thiazide-like diuretics) - in 300 pts w/ ADHF

Question 33

ROPA-DOP

Answer 33

JACC 2018 - furosemide infusion (vs bolus q12h) was a/w worse renal function (because infusion does not allow adequate re-equilibration of intra/extravascular volumes in congestion) - in 90pts w HFpEF >50% and ADHF - This was especially true for women, African Americans, and CKD. - Low dose-dopamine (3mcg/kg/min) had no impact on renal function.

Question 34

ROSE

Answer 34

JAMA 2013 - neither low-dose dopamine (2 mcg/kg/min) nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy - in 360 pts w ADHF and renal dysfunction (eGFR 15-60)

Question 35

DAD-HF

Answer 35

2010 - low-dose dopamine 5 mcg/kg/min + low-dose furosemide 5 mg/h x8h (vs high-dose furosemide 20mg/h x8h w/o dopamine) was a/w better renal function profile and less hypokalemia - in 60 pts w ADHF

Question 36

DAD-HF II

Answer 36

2014 - high-dose furosemide 20mg/h (vs low-dose furosemide 5mg/h) was not a/w differences in hospital and post-discharge outcomes. - Addition of low-dose dopamine infusion was NOT a/w any benefits.

Question 37

OPTIME-CHF

Answer 37

JAMA 2002 -in ADHF, routine use of milrinone as adjunct to standard therapy was NOT a/w lower mortality (in hospital of at 60 days), or death/readmission. -milrinone be harmful in ischemic HF, but neutral to beneficial in nonischemic CMP

Question 38

CHAMPION

Answer 38

2017 | -PA pressure-guided HF management reduces morbidity and mortality in pts with HFrEF on GDMT