258B - HFrEF Management Flashcards
Treatment of symptomatic HFrEF
- Renocentric (diuresis)
- Haemodynamic (digoxin, inotropic)
- Neurohormonal antagonism (disease modifying pillars)
- Iron replacement for iron deficiency
- Vaccination
- Heart rate reduction
- AICD or CRT
- LVAD
- Cardiac transplant
ACEIs and ARBs in HFrEF
- mechanism
- High vs low dose trials: ACEIs (ATLAS), ARBs (HEAAL)
Mechanism
1. RAAS pathway inhibition
- Prevents cardiac remodeling
- Reduces preload, afterload, systolic wall stress
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
- Landmark trial
- High vs low dose beta blocker trial (MOCHA)
Mechaniams
1. Negative chronotrophy blocks sympathetic neural pathway and reduces heart rate (counteracts adrenaline)
2. Prevents overstimulation of catecholamines
3. Reduces CAMP mediated calcium overload
Does not exhibit class effect - BBs with intrinsic sympathomimetic activity do not demonstrate survival benefits.
Limited to: metoprolol, bisoprolol, carvediolol
Landmark trial: COPERNICUS trial
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
- Randomised Aldactone Evaluation Study (RALES)
- Eplerenone study
HFrEF - RAAS activation: elevated aldosterone levels promote sodium retention, electrolyte imbalance, endothelial dysfunction
–> contributes to myocardial fibrosis
Mechanism
1. Aldosterone antagonism - promotes salt and water excertion
2. reduces 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
Cytokine inhibitors in HFrEF
Infliximab, etanercept - worsened HF
IVIg - no beneficial outcome
Canakimumab anti-inflammatory thrombosis outcome (CANTOS)
Post-MI with elevated CRP treated with canakimumab associated with dose-dependent reduction in HF hospitalisation and mortality
HMG-CoA reductase inhibitors in HFrEF
CORONA trial (rosuvastatin)
No improvement in aggregate clinical outcomes
No rationale for routine statin therapy in non-ischaemic HF
Statin reduces major CVS event and survival in non-HF populations, but not beneficial in HF
Theoretically detrimental: depletion of ubiquinone in electron transport chain
Antiplatelet and anticoagulation in HFrEF
HFrEF - hypercoagulable state with high risk of VTE events
Significant harms of anticoagulant use vs aspirin
- WARCEF trial (warfarin): higher risk of haemorrhage, with similar primary outcomes
- Rivaroxaban: no reduction in stroke or ischaemic events
Current guidelines support the use of aspirin in patients with ischemic cardiomyopathy who do not have a contraindication
Adjuct approaches in HFrEF
- Fish oil
- Micronutrients
- Exercise rehabilitation
- Fish oil - modest improved outcome
- Thiamine and selenium supplementation improves cardiac function
- Exercise rehabilitation - HF-ACTION: safe, improved well being and lower mortality
What are the indications for (implantable cardioverter-defibrillator) AICD insertion in HFrEF?
What are the selection criteria for AICD insertion in HFrEF?
- Primary prevention of conditions that may lead to sudden arrhythmic death
(long QT, Brugada, HOCM, ARVD) - Secondary prevention for:
- Survivors of cardiac arrest
- Sustained symptomatic ventricular arrhythmias (VT, VF)
Selection criteria: All of the criterias below
1. NYHA class II and III
(NOT class IV as significant higher pump failure death offsetting benefits)
2. Both ischaemic (class 1 recommendation) and non-ischaemic (Class 2a recommendation)
3. LVEF <35% for >3 months of GDMT
4. QRS complex < 130ms
5. Expected to survive longer than 1 year with good functional status
What are the selection criterias for cardiac resynchronisation therapy (CRT) insertion or upgrade from AICD in HFrEF?
What are the endpoint benefits of CRT insertion?
Criterias
1. Sinus rhythm
(or high degree AV block and even AF)
2. QRS > 150ms with or without LBBB complex
(130-149ms class 2a recommendation)
3. LVEF < 35%
4. Regardless of NYHA class
5. Worsening HF with pacemaker or AICD with significant proportion of RV pacing
Exclusion criteria: QRS < 130ms
Benefits:
1. Reduces cardiac dyssynchrony, improves cardiac output
2. Recersal of cardiac remodeling
3. Improves mean survival 4-5 years
- What rhythms require pacing?
- Selection choice for CRT-D vs CRT-P
Pacing for:
1. Symptomatic bradycardia
2. Significant pauses
3. Atrio-ventricular block
Selection choice favouring CRT-P (cheaper):
1. NICMP
2. Short life expectancy / older age
(Balancing use of CRT-D in pts with prev cardiac arrest or defibrillable rhythms of pulseless VT and VF)
3. Major comorbidities
4. Renal impairment
5. Patient preference
Why QRS > 130ms for CRT insertion? (Echo-CRT trial)
Possible harm from CRT when QRS < 130ms
- Deleterious effect of AF on CRT
- Effects of CRT on AF
- Potential treatment to overcome
Deleterious effect
1. Suboptimal biventricular pacing
- Rapid, irregular intrinsic activation of ventricles in AF reduce delivery of biventricular pacing (AF ventricular rate inverse correlate to pacing percentage)
- This is in spite of up to 99.6% pacing (demonstrating need to obtain close 100% pacing as possible)
2. Loss of AV synchrony
- Loss of atrial systole as contribution to cardiac output (as much as 20-30%)
3. Increased inappropriate defibrillator therapies
CRT on AF
1. Potential restoration of SR (10.7%) from reverse LV remodeling, improved LA function
2. Improvement in MR
3. Reduces elevated sympathetic activity
Treatment to overcome
1. Aggressive rate control with:
- Beta blockers
- Digoxin
If ventricular rate remains high despite rate control:
2. Aggressive rhythm control with
- Anti-arrhythmias: amiodarone
- AV node ablation and repeat ablation
Explain the types of cardiac dyssynchrony in heart failure
A. Electrical dyssynchrony
B. Mechanical dyssynchrony
C. Cardiac remodeling
A. Electrical dyssynchrony: widened QRS
Normal: uniform high velocity electrical conduction propagating through His-Purkinje system - synchronised depolarisation of ventricles
Pathological:
- Altered electrochemical substrate and impaired conduction fibres results in varying velocity and non-uniformity areas of activation delays
- Lengthening of QRS complex, LBBB formation
B. Mechanical dyssynchrony
1. Intraventricular dyssynchrony within LV
- Delay between early-activated interventricular septum and late-activated posterolateral wall due to LBBB
2. Interventricular dyssynchrony between LV and RV
- Earlier activation of RV, with delayed activation of LV due to LBBB
3. AV dyssynchrony due to:
- prolonged/absent AV nodal conduction
- His-Purkinje system dysfunction leading to asynchronous activation of 2 ventricles, resulting in frequent PVCs, R on T
C. Cardiac remodeling
1. Left ventricle dilatation
2. Worsening systolic and diastolic function
Explain the pathophysiology of cardiac dyssynchrony
- Prolonged isovolumic contraction and relaxation - no movement of blood
- Reduction in cardiac pump efficiency
- MR in dyssynchronous LV
- Lack of leaflet coaptation
- Papillary muscle dysfunction
Clinical significance of frequent PVCs and R on T
- Ineffective pump
- Potential trigger of re-entrant tachydysrhythmia (VT, AVNRT, AVRT, TdP)
How does CRT improve ventricular dyssynchrony?
(placement of leads and its action)
Leads placement:
1. LV pacing lead - through coronary sinus onto lateral or posterolateral wall of LV
2. RV pacing lead - apex of right ventricle
3. RA pacing lead - in RA
CRT coordinates contraction of ventricles (LV and RV) to augment cardiac output
Clinical trials on CRT benefits in HFrEF
Improvement in NYHA class and 6MWT in:
- MUSTIC
- MIRACLE
Reduced combined endpoint of hospitalisation or death from HF in:
- COMPANION
- CARE-HF
- MADIT-CRT
- RAFT
About 30% patients did not achieve expected results post-CRT insertion.
What are the possible causes of CRT non-responders?
- Inconsistent pacing due to intrinsic HR exceeding programmed rate
- Management: increasing beta blockers - Lack of mechanical dyssyncrhony
- No potential markers to reliably predict response - High myocardial scar burden in ICMP
- Predicts via MRI heart or PET scan
- Lead tip placed in scar region unable to pace ventricle effectively (or if at all) - Suboptimal LV lead position
- Limited by accessibility of suitable epicardial coronary veins
- Management: operative placement of epicardial lead
MADIT-CRT recommendations for LV lead positioning
Avoid apical positioning of LV lead - increased HF events and death
Favoured basal positioning of LV lead
ALSYNC trial and its risk
Dramatic clinical improvement with endocardial placement of an LV lead, even in CRT non-responders
Risks:
1. Thromboembolism
2. Device-related infection
3. Injury to the mitral valve apparatus
What are some potential advanced HF management?
- Mechanical circulatory device (left ventricular assist device LVAD)
- As destination therapy (DT) - long term option, improves 1 year survival >80%
- As bridge to transplant (BTT) or candidacy (BTC) - Heart transplantation
