258B - HFrEF Management Flashcards
Treatment of symptomatic HFrEF
- Renocentric (diuresis)
- Haemodynamic (digoxin, inotropic)
- Neurohormonal antagonism (disease modifying)
ACEIs and ARBs in HFrEF
- mechanism? not done
- High vs low dose trials: ACEIs (ATLAS), ARBs (HEAAL)
ACEi confers 23% reduction in mortality and 35% reduction in combined endpoint of mortality and hospitalitsation in HFrEF
ARBs are suitable alternatives for ACEi intolerance (cough, angioedema)
ATLAS and HEAAL Dosing trials
Higher dose has lower dates of death and HF hospitalisation
In the absence of hypotension (fatigue, giddiness), aim to uptitrate every 2 weeks as tolerated
Beta blockers in HFrEF
- mechanism? not done
- High vs low dose beta blocker trial (MOCHA)
Does not exhibit class effect - BBs with intrinsic sympathomimetic activity do not demonstrate survival benefits.
Limited to: metoprolol, bisoprolol, carvediolol
MOCHA dosing trial
Higher dose has lower dates of death and HF hospitalisation
In the absence of hypotension (fatigue, giddiness), aim to uptitrate every 2 weeks as tolerated
Cardiac Insufficiency Bisoprolol Study (CIBIS)
- Which to start first? beta blockers or ACEIs?
No significant difference in outcoms based on sequence of drug initiation
Important to optimally titrate doses of medication
MRAs in HFrEF
- Pathophysiology
- Mechanism not done
- Randomised Aldactone Evaluation Study (RALES)
- Eplerenone study
HFrEF - RAAS activation: elevated aldosterone levels promote sodium retention, electrolyte imbalance, endothelial dysfunction
–> contributes to myocardial fibrosis
Spironolactone (RALES)
Reduction in morbidity and mortality
Side effect: gynaecomastia, erectile dysfunction, diminished libido
Eplerenone
No anti-androgen effect
RAAS neurohormonal escape theory
- Controversies in dual ACEI+ARB
(Val-HeFT, CHARM-Added) vs (VALIANT, ATMOSPHERE)
Angiotensin II can be generated by non-ACE pathways, thus may escape blockage and increases back to pre-treatment levels during long term ACEI therapy
Valsartan HF (Val-HeFT) and Candersartan (CHARM-Added) trial
ACEI + ARB lowers risk of HF hospitalisation
However lacking evidence based ACEI dose
Valsartan in AMI (VALIANT) and Aliskiren (ATMOSPHERE) trial
Combination therapy increases in adverse effect without added benefit
Higher rates of hyperkalaemia, hypotension, worsening renal function
Vasodilator trial: hydralazine and nitrates in HFrEF
- Mechanism of hydralazine
- Mechanism of nitrates
- A-HeFT
Hydralazine reduces systemic vascular resistance, induces arterial vasodilatation
Nitrates transformed in SMC into NO that stimulates CGMP production and consequent arterial-venous dilation
African-American HF Trial (A-HeFT)
Fixed ISDN + hydralazine TDS regime showed improvements in survival and hospitalisation
ARNI in HFrEF
- OVERTURE Trial: omapatrilat vs Enalapril Randomised Trial of Utility in Reducing Event
- PARADIGM-HF (Entresto)
OVERTURE Trial (unsucessful)
Increased risk of angioedema
No reduction in primary outcome or combined risk of death/hospitalisation
PARADIGM-HF (successful)
Entresto 20% reduction in composite primary endpoint
16% reduction in all cause mortality
Clinically important QOL improvement
Heart Rate Modification in HFrEF
- Ivabradine (SHIFT trial)
Ivabradine (SHIFT trial)
NYHA class II or III HFrEF
Prior HF hospitalisation
Sinus rhythm with HR > 70/min
Reduced combined endpoint of CVS death and HF hospitalisation in proportion to degree of heart rate reduction
Original protocol requirement to be treated with maximally tolerated beta blocker, however:
10% patients were not treated with beta blockers
75% treated with beta blockers at subtarget dose
-> Implications: ivabradine may serve as adjunct or alternative to beta blocker intolerance
SGLT2i in HFrEF
- EMPA-REG
- EMPEROR-REDUCED
- DAPA-HF
EMPA-REG
Empagliflozin 35% reduction in HF hospitalisation in HFrEF with type 2 DM
Cardiovascular benefits unrelated to degree of reduction in HbA1c
EMPEROR-REDUCED
Empagliflozin 25% reduction in primaryu composite endpoint in HFrEF with EF <40%
Consistent with or without diabetes
DAPA-HF
Dapagliflozin 26% reduction in primary composite endpoint in HFrEF with GDMT
Consistent with or without diabetes
Soluble Guanylyl Cylase Stimulation (Vericiguat) in HFrEF
- Mechanism of action
- VICTORIA study
MOA:
- sGC key enzyme of NO signaling pathway, catalyses synthesis of cGMP producing vasodilation
- Vericiguat stimulates and sensitises sGC to endogenous NO, enhancing cGMP and NO signaling
VICTORIA study
NYHA II-IV, EF < 45%, elevated BNP, worsening HF despite GDMT
Vericiguat target dose 10mg modest 10% relative risk reduction in primary composite outcome
(Await further review and regulation as of 2024)
Myosin activator (omecamtiv mecarbil) in HFrEF
- Mechanism of action
- COSMIC-HF
- GALACTIC-HF
Omecamtiv mecarbil prolongs ejection period and increases fractional shortening without altering force of contraction
Not associated with increased myocardial oxygen demand
COSMIC-HF
Significant improvements in cardiac function and indices of LV remodeling
Reduction in BNP
Modest increase in cardiac troponin
Safety profile comparable to placebo, no increase in cardiac adverse events
GALACTIC-HF
HFrEF EF < 35% given omecamtiv mecarbil 25-50mg BD vs placebo
14% reduction in primary composite endpoint of death, more on HF hospitalisation/event
(Additional study needed)
Digoxin in late HFrEF
- DIG trial
Mild inotropic effect, attenuate carotid sinus baroreceptor activity,
Sympathoinhibitory - reduces serum norA, plasma renin, and aldosterone
DIG trial
Reduction in HF hospitalisation
No reduction in mortality or QOL improvement
Paradoxical higher mortality and hospitalisation in women
Diuretics in HFrEF
Diuresis mainly for ADHF
No data to suggest diuretics improve primary composite outcome
Calcium channel antagonists in HFrEF
Reduces blood pressure but do not affect morbidity, mortality or QOL
First generation - verapamil and diltiazem
- Exerts negative inotropic effect
- Destabilises asymptomatic patients, thus discouraged in HFrEF
