GDMT in HFrEF

GDMT refers to the set of medical and device interventions that have been shown to decrease important MACE +/- improve mortality in heart failure with reduced ejection fraction (of mostly all types). These are informed by guidelines from the CCS, AHA, and the ESC.

The goal of GDMT and HFrEF treatment is optimisation of LVEF, reduction of symptoms (NYHA I goal), and to decrease the risk of sudden cardiac death.

First-Line GDMT

RAAS Inhibition

Prior evidence and guidelines recommended initiation of ACEi or ARB. New evidence suggests strongly that all patients should be on ARNI therapy preferentially, and this is reflected in most recent guidance from the CCS (2021 Focused Update).

Guideline (CCS) Recommendations: 1. We recommend an ACE inhibitor, or ARB in those with ACEi intolerance, in patients with acute MI with HF or an EF < 40% post-MI to be used as soon as safely possible post- MI and be continued indefinitely. 2. We recommend that an ARNI be used in place of an ACEi or ARB, in patients with HFrEF, that remain symptomatic despite treatment with appropriate doses of GDMT in order to decrease cardiovascular death, HF hospitalizations, and symptoms. 3. We recommend that patients admitted to hospital for acute decompensated HF with HFrEF should be switched to an ARNI, from an ACEI or ARB, when stabilized and before hospital discharge (Strong Recommendation; Moderate-Quality Evidence). 4. We suggest that patients admitted to hospital with a new diagnosis of HFrEF should be treated with ARNI as first-line therapy, as an alternative to either an ACEI or ARB (Weak Recommendation; Moderate-Quality Evidence).

Evidence Base in rEF and pEF:

Trial	Drug	Findings
TRANSITION	Sacubitril-valsartan	Initiation of sac-val in-hospital for decomp HF is as safe as starting it as an outpatient after discharge.
PARADIGM-HF (rEF)	Sacubitril-valsartan	Sac-val compared with enalapril, led to a 20% RRR in HF hospitalization or CV death
Val-HeFT (2001)	Valsartan
SOLVD (1991)	Enalapril
PARAGON-HF (pEF)	Sacubitril-valsartan	PARAGON-HF showed a modest but nonsignificant 13% reduction in the primary outcome, which was driven by a reduction in first and recurrent HF hospitalizations.
CHARM-Preserved	Candesartan	ARB (candesartan) reduces hospitalizations in HFpEF.

Beta-Blockade

Beta-blockers have a strong evidence base in HFrEF. In particular, there are three that are most evidenced in heart failure with reduced EF.

In all trials, the mortality benefit from beta-blockers stemmed from a reduction in both progression of HF & sudden cardiac death. In all these trials, patients were already on diuretics + ACE inhibitors/vasodilators. LVEF was generally <25-40%. Symptoms ranged from NYHA II-IV across studies. HF was stable for 2-3 months and not acutely decompensated.
Many patients were on digoxin (due to the era of the trials -- late 1990s). At least 1/2 of the patients had ischemic cardiomyopathy.
Excluded patients: ADHF, previous/for heart transplant, SBP < 100, HR < 60-68, untreated 2-3 degree AVB, HF secondary to primary valvular disease, myocarditis, or reversible cardiomyopathy.

Trial	Drug	Outcome
CIBIS-II	Bisoprolol
Carvedilol HF Study	Carvedilol
COPERNICUS	Carvedilol
MERIT-HF	Metoprolol succinate (long-acting)
COMET	Carvedilol vs metoprolol tartrate	Lower mortality with carvedilol (NNT=17) over 5 years as compared to short-acting metoprolol tartrate.

Beta-Blockers in Hospitalized Patients

START beta-blockers before discharge, in stabilized patients, because it improves short and intermediate-term outcomes without intolerance or extended LOS
1. IMPACT-HF: predischarge initiation of carvedilol in stabilized patients improved the uptake of beta-blockers at 60 days, without increasing side effects of LOS
CONTINUE/RESTART beta-blockers before discharge, as doing so reduces in-hospital and 60-180 day mortality
1. B-CONVINCED: in ADHF, continuation of beta-blockers is noninferior with regards to clinical improvement, 3-month mortality, BNP, LOS, but increases beta-blocker therapy at 3 months.
2. OPTIMIZE-HF: continuation of beta-blockers in patients with ADHF but without cardiogenic shock reduces risk of adverse postdischarge clinical outcomes

Nuances of Beta-Blockade

Carvedilol is most lipophilic and therefore most likely to cause vivid dreams/hallucinations/CNS effects of beta-blockade
Fatigue generally is an adverse effect associated with initial dosing, and will resolve after 1-2 weeks.
Beta-blockers might reduce the sympathetic symptoms of hypoglycemia.
Risk of beta-blocker withdrawal decreases with longer half-lives

Mineralocorticoid Receptor Antagonism

Trial	Drug	Outcome
RALES	Spironolactone	Spironolactone reduces all-cause mortality by 30% in NYHA class III-IV and EF <35%.
TOPCAT (pEF)	Spironolactone	Spironolactone reduces hospitalization in HFpEF. Post-hoc analyses (not powered) suggest mortality benefit in North America.

SGLT2 Inhibition

Trial	Drug	Outcome
DAPA-HF	Dapagliflozin	Among individuals with HFrEF (NYHA II-IV, LVEF ≤40%) with or without T2DM, the addition of the SGLT-2 inhibitor dapagliflozin decreased rates of CV death or worsening HF, as well as all-cause mortality.
SOLOIST-WHF	Sotagliflozin	In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo.
EMPEROR-Reduced	Empagliflozin	Among patients with symptomatic heart failure with reduced ejection fraction (HFrEF) (with or without type 2 diabetes), empagliflozin reduced the risk of a composite of CV death or HF hospitalization vs placebo (NNT 19) at 1.3 years.
EMPULSE	Empagliflozin	New-start empagliflozin in patients hospitalized with decomp HFrEF is well tolerated.

Second-Line GDMT

Digoxin

Trial	Drug	Outcome
DIG	Digoxin	Digoxin reduces hospitalizations in patients with HFrEF

H-ISDN

Hydralazine-isosorbide dinitrate.

Ivabradine

This is a "funny"-sodium influx channel blocker. It serves to slow down the autodepolarization of cardiac pacemaker cells, which slows down the heart rate (only if in sinus rhythm).

Vericiguat

Trial	Drug	Outcome
VICTORIA	Vericiguat	Among patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who received vericiguat than among those who received placebo.

Omecamtiv mecarbil

Trial	Drug	Outcome
GALACTIC-HF

Device Therapy

https://www.nature.com/articles/s41572-019-0084-1/tables/2