Heart Failure Tx Flashcards
Pharmacotherapy of HFrEF
Reduced Ejection Fraction
• Patients should receive (“quad therapy”): – angiotensin antagonist (ARNI/ACEI/ARB) – beta blocker – mineralocorticoid receptor antagonist (MRA) – sodium glucose transport 2 inhibitor (SGLT2) • If symptoms continue to be poorly controlled, consider in select patients: – ivabradine – hydralazine/nitrate – digoxin • Diuretics – Required for majority of patients
Diuretics - Mechanism of Action
Reduce preload to improve symptoms
associated with fluid retention.
DO NOT ALTER MORTALITY
ONLY PT PRONE TO SYMPTOM OVERLOAD
loop diuretics most common
oop Diuretics
• Pharmacology:
– inhibits Na/K/2Cl cotransporter system in the
ascending loop of Henle - ↑ Na/Cl/K excretion
– PG mediated ↑renal blood flow
– ‘loop diuretics’ are the most efficacious diuretics, remove Na and water
– effective with impaired renal function
• Furosemide most common; ethacrynic acid & bumetanide (rarely used) • Indications: – acute and chronic treatment of pulmonary and peripheral edema in HF (symptom control)
Furosemide: Dose
considerations
Kinetics:
– bioavailability: 50% (furosemide 40mg po= 20mg IV)
• absorption variable especially in HF
• as renal function declines higher doses needed.
• Adjust according to fluid status of patient, no fixed dose:
– symptoms (e.g. SOB, fatigue); signs (e.g. weight:
↑ >2lbs over 2days or 5lbs/7days rapid gain, JVP, edema); labs (↑ Scr, BNP).
– if fluid overloaded assess precipitating factors:
• salt/fluid intake
• medications (NSAIDs, under-use of furosemide)
• Goal: attain & maintain “dry weight”, ideal weight without signs of fluid accumulation
Furosemide: Dose
• Dose (iv): 40 – 80 mg initially
– range: 20-40mg bid, tid (also given by infusion at 5-40mg/h)
• Dose (oral): 20-160mg (40mg average) qam. Larger
doses-bid, Second dose of the day by 1600h.
split doses is more eff than bolus dose
Use lowest possible dose.
Other Diuretics
metolazone: a thiazide-like diuretic:
– ↓ Na+ reabsorption in DCT
– 2.5 - 10mg daily in combination with loop
diuretics can produce synergistic effects
– monitor electrolytes and renal function!
• thiazides:
– hydrochlorothiazide, chlorthalidone may also be
used in combination with furosemide (rarely
used alone)
– not effective in CrCl < 30ml/min
• spironolactone
Acutely, much higher doses may be
required due to _____________
diuretic ‘resistance’:
• patients with advanced HF often do not perfuse their kidneys well, higher doses (freq admin), combination diuretic therapy or iv inotropes may be required
Diuretics - Monitoring
Efficacy (goal: euvolemia)
• resolution of Sx (dyspnea, orthopnea),
peripheral edema, JVD, ↓weight (dry weight)
• requires close follow up & dose adjustments
Adverse Effects: • hypovolemia – symptomatic hypotension (postural), fatigue, confusion, ↓urine output, weight (stable or below dry wtg), decline in renal function. • electrolytes: ↓K, ↓ Mg • hyperuricemia, gout (no NSAIDS) • tinnitus/hearing loss (high doses)
Joe (68y) presents to clinic for his scheduled visit. He has been relatively stable since his last visit 6 mos ago. He informs that he’s had recent flair up of gout. Your assessment: - JVP= 6 cm, +2 pitting edema - BP: 115/78, HR: 72 bpm - weight: 85 kg (dry weight = 82kg) - Sx: more SOBOE over the last 2wks - SrCr= 88mmol/L (3 mos ago= 75) - furosemide: 40 mg po daily x 1 year - med changes: Advil 400 mg tid
Do you think Joe is:
A. Hypovolemic
B. Euvolemic
C. Hypervolemic
C. Hypervolemic
JVP > 4
weight increase
Joe (68y) presents to clinic for his scheduled visit. He has been relatively stable since his last visit 6 mos ago. He informs that he’s had recent flair up of gout. Your assessment: - JVP= 6 cm, +2 pitting edema - BP: 115/78, HR: 72 bpm - weight: 85 kg (dry weight = 82kg) - Sx: more SOBOE over the last 2wks - SrCr= 88mmol/L (3 mos ago= 75) - furosemide: 40 mg po daily x 1 year - med changes: Advil 400 mg tid
What else would you ask Joe? A. How much Advil Joe has taken B. Has Joe had the flu recently C. What he plans to eat while watching the Superbowl D. Compliance with HF Medications
A. How much Advil Joe has taken (last few days or week)
B. Has Joe had the flu recently (some pyt can become severely dehydrated)
C. What he plans to eat while watching the Superbowl
D. Compliance with HF Medications
Joe (68y) presents to clinic for his scheduled visit. He has been relatively stable since his last visit 6 mos ago. He informs that he’s had recent flair up of gout. Your assessment: - JVP= 6 cm, +2 pitting edema - BP: 115/78, HR: 72 bpm - weight: 85 kg (dry weight = 82kg) - Sx: more SOBOE over the last 2wks - SrCr= 88mmol/L (3 mos ago= 75) - furosemide: 40 mg po daily x 1 year - med changes: Advil 400 mg tid
What do you recommend?
Mark all that apply
A. Increase furosemide to 60 mg/day
B. Increase furosemide to 100 mg/day
C. Add metolazone 2.5mg daily for 3 days.
D. Assess gout, provide alternative therapy
E. Tell Joe to enjoy the Superbowl and take extra
furosemide if he drinks more than 4 beers and eats
lots of salty snack
A. Increase furosemide to 60 mg/day (increase it by 20-40mg generally)
- ask him to weigh himself everyday in morning for f/u
don’t add metolazone, kidneys are ok
D. Assess gout, provide alternative therapy
- gout is precipitating factor, if cleared up we may not need anything therapy
- avoid these drugs in the future
E. Tell Joe to enjoy the Superbowl and take extra
furosemide if he drinks more than 4 beers and eats
lots of salty snack
- encourage Joe not to eat salt snacks first
ACE Inhibitors
pharma nd indications
Pharmacology:
• block the formation of angiotensin II (from
ang. I), a strong vasoconstrictor:
– result is vasodilation and decreased Na and
water retention (via aldosterone)
– favourably influence remodeling process
Indications:
• First-line therapy for HFrEF (NYHA-FC I-IV)
and asymptomatic left ventricular systolic dysfunction
– numerous randomized controlled trials have
conclusively demonstrated the benefit of ACE
inhibitors on mortality and morbidity
(symptoms) & reduction in HHF
ACE Inhibitor
dosing
start at initial dose and titrate up
Titrate: BP – no target BP (watch for symptomatic hypotension), renal fxn, K+
a little is better than nothing for dose
abs: at baseline & 1-2 weeks of dosage increase
there is no target bp for HF, ensure asymptomatic
ACE Inhibitors
AE
contra
Adverse Effects:
– hypotension (asymptomatic SBP 90-100 mmHG generally
acceptable, consider patient factors such as frailty)
– worsening of renal function (early:↓eGFR <30% or
↑Scr< 30% acceptable)
– hyperkalemia (>5.2 mmol/L)-contributing factors
– dry cough (10 - 20%)
– taste disturbances, skin rashes
– angioedema (rare)
additive effects with beta blockers, diuretics, MRA,
SGLT inhibitors (hypotension/renal fxn)
Contraindications: previous angioedema,
pregnancy, bilateral renal artery stenosis. Use with
great caution in severe aortic stenosis
Angiotensin Receptor
Blockers (ARB)
Pharmacology:
• A-II antagonists block the AT1 receptor, responsible for many of the deleterious actions of A-II.
– other, non-ACE pathways can form A-II
– theoretical advantage is that ARB could
block A-II produced from any pathway
Indications: Hypertension, HFrEF
Role of ARB in HFrEF
- vs. ACE inhibitors (ELITE II- captopril vs. losartan): not better, not equivalent
- vs. placebo (CHARM – Alternative) candesartan: better than placebo
• In combination with ACE inhibitors:
– ValHeFT (valsartan): reduction in hospitalizations
vs. ACEI alone
– CHARM-Added: reduction in mortality and
hospitalizations vs. ACEI alone
– Increase ADRs: ↑ Hypotension 2X,
↑ Hyperkalemia 4X, ↑ Renal dysfunction2X
Angiotensin Receptor
Blockers (ARB)
AE
hypotension, ↑Scr (worsening of renal
function), hyperkalemia
Current Status of ARBs in HFrEF
• May represent an alternative in patients unable to tolerate ACE inhibitors (mostly due to intolerable cough) – Angioedema – cross sensitivity reported
b-adrenergic Antagonists
(‘Beta Blockers’)
pharm
indications
• Pharmacology: competitively blocks the beta adrenergic receptor:
– reduction of heart rate, blood pressure, myocardial O2 consumption
– ↓ renin activation
– antiarrhythmic effects
• Indications:
– First-line therapy for HFrEF (NYHA-FC I-IV): reduce mortality**, hospitalizations and progression of HF
– asymptomatic left ventricular systolic dysfunction
– therapy for ischemic heart disease and hypertension (<60 years of age)
– secondary prevention after myocardial infarction
– antiarrhythmic
Beta Blockers
what are the 3 types
which ones can be used?
• b1 selective (‘cardioselective’):
– primarily blocks cardiac beta receptors (this
property is lost at higher dose)
• Intrinsic Sympathomimetic Activity (ISA):
– a partial agonist (less than complete beta
receptor blockade)
• a antagonist:
– vasodilator properties
not class action need to use
meto, carvedilol, bisprolol
Beta BlockersAE
worsening of HF symptoms initially (warn patients)
• fatigue, lethargy, transient fluid retention
– hypotension
– bradycardia (reasonable target 50-60bpm, asymptomatic)
– AV block (heart block)
– depression
– nightmares
– bronchospasm
– worsening of peripheral arterial disease symptoms
– masking of hypoglycemia in diabetics
Additive effects with digoxin (on AV block), ivabradine
(bradycardia) and ACE inhibitors (hypotension)
BB
Contraindications
– uncontrolled asthma, bradycardia, AV conduction disturbances, severe peripheral arterial disease, poorly controlled diabetes
• May worsen symptoms of HF initially:
– initiate in patients with stable HFrEF.
– patient should be clinically euvolemic prior to initiating. Relieve congestion with diuretics.
– start low, go slow
– metoprolol 6.25-12.5mg BID, carvedilol 3.125-6.25mg BID, bisoprolol 1.25 - 2.5mg daily
– increase every 2-4 weeks
– if patient has a severe exacerbation of HF symptoms,
stop titration or temporarily reduce dose by 50% (don’t
stop BB)
– if mildly worsened symptoms, adjust dose of diuretic
and/or stop titration
– inform patient of what to expect (initiation and during
titration)
Carvedilol Or Metoprolol
European Trial: COMET
Design: multicentre, randomized, double-blind trial
• Patients: 3029 with stable NYHA-FC II-IV, 1 or
more CV hospital admission in past 2y,
EF<0.35, HR>60, BP>85 systolic, most on ACEI
• Interventions:
– carvedilol 3.125mg BID (target 25mg BID), or
– metoprolol tartrate 5mg BID (target 50mg BID)
• Outcome Measures: all cause mortality at 58
months
Mineralocorticoid Receptor
Antagonists (MRA)
Spironolactone and eplerenone Pharmacology: • block the mineralocorticoid receptor (target site for aldosterone) – potassium-sparing diuretic (mild) – chronic elevations of aldosterone are deleterious (cardiac fibrosis and ventricular remodeling) Indications: • HTN, cirrhosis, HF
benefits start early on in therapy, effects apparent in 3 months
Spironolactone
dose
ae
contra
• Dosage:
– 12.5-25 mg once daily (can increase up to
50mg daily)
- Adverse Effects:
- hypotension, hyperkalemia (does dependent), increased serum creatinine, dehydration, estrogen-like effects (gynecomastia, impotence)
• Contraindications: caution with K
supplements
Eplerenone
place in therapy
Selective aldosterone receptor antagonist
does not have estrogen/androgen like effects like spironolactone
37% ↓ CV mortality or HF hospitalization (HR
0.63, 95%CI 0.54 – 0.74)
Place in therapy: – Alternative to spironolactone (intolerance to hormonal ADR) – Consider cost ($80/mos vs $17/mos) – Special authorization for ABC coverage
RALES trial showed?
Hospital admissions for hyperkalemia increase 3x
pt hosptialized for heart failure who received ACEi
In-hospital deaths associated with hyperkalemia increase 3x
Reduction of Hyperkalemia
l avoid use with:
– baseline K+ > 5 mmol/L
– CrCl < 30 ml/min, Scr > 220 μmol/L
– nephrotoxic drugs
l ↑ risk:
– Scr > 140 μmol/L
– high dose ACEI (lisinopril/enalapril 10mg/d)
– diarrhea and dehydration
l Close monitoring: at 1 week after initiation or dose
change
l Avoid/reduce K+ rich foods, stop NSAIDS & K+
supp.
l In select patients, start spironlactone at 12.5mg
and titrate to 25mg, eplerenone (25mg/d)
Mineralocorticoid Receptor
Antagonists (MRA)
Indications
• Post MI with EF < 40% (Sx of HF or diabetes)
• CCS Guidelines (2021):
– component of the “standard therapy” (Quad therapy) for
patients with HFrEF, NYHA-FC I to IV
Hydralazine/Nitrates
• Pharmacology:
– hydralazine - direct arterial vasodilator
– nitrates - venous vasodilator
- combination studied in the VHeFT study (1986), which showed a reduction in mortality, compared to placebo
- however, VHeFT 2 showed that enalapril was superior…
African American Heart Failure Trial
A-HeFT
• Design: Randomized, placebo-controlled
multicentre trial
• Patients (n=1050):
– self-identified as of African descent
– NYHA-FC III or IV
– Already receiving ACEI/ARB, beta blockers, etc.
– Ejection fraction of <0.35 or <0.45 with ventricular dilation
• Interventions: random assignment to either
– 37.5mg hydralazine + 20mg isosorbide dinitrate three times daily (target dose: 75mg + 40mg three times daily)
– Placebo
• Outcome measures: mortality, composite of
outcomes
Trial stopped early for benefit
Only 68% obtained target
doses; 2x ADEs in treatment
arm
Hydralazine/Nitrates
• Place in HF therapy:
– African-Americans with moderate to severe
symptoms despite standard therapy (ACEI,
beta blockers, etc.).
– patients unable to tolerate ACEI/ARB due to
hyperkalemia, renal insufficiency.
• Adverse effects:
– headache, GI distress, flushing, dizziness.
• Compliance (?): requires frequent dosing
Digoxin
add on therapy
pharmacology
indications
Pharmacology:
– inhibits the Na-K ATPase pump in the cardiac cell
membrane, leading to increased cytosolic calcium
and stronger cardiac myocyte contraction
(inotropic effect):
– neurohormonal effects in HF (↓SNS activation)
– depresses SA node function (reduces heart rate)
and AV node conduction
Indications: adjunctive therapy for HF:
– DIG study showed reductions in hospitalization
for HF by 27% (NEJM 1997;336:525-33), not
mortality.
– Consider in patients with moderate to severe
symptoms (already on optimal HF therapy)
– also used to control ventricular rate in AF
Digoxin
dose
ae
Dosage:
– maintenance dose (iv/oral): 0.0625 -
0.25mg daily (dose adjust for ↓ renal fxn)
• Adverse Effects:
– GI: anorexia, nausea, vomiting
– CNS: confusion, visual disturbances
– CVS: arrhythmias (AV block, PVCs, etc.)
– toxicity enhanced by hypokalemia,
hypothyroidism
– additive effects with beta blockers (heart
rate & AV conduction slowing)
Digoxin
contra
Contraindications: AV conduction disturbances
• Other:
– digoxin has a long half-life of 1.5 days
– digoxin is a narrow therapeutic range drug
– elimination primary by kidney (caution in renal dysfunction and elderly)
– serum concentrations
• digoxin serum levels were associated with ↑ toxicity (> 1.5 nmol/L)
• 0.6 -1.02 nmol/L associated with ↓ mortality
• drug levels should only done to assess toxicity
Digoxin drug interactions (!):
– quinidine, verapamil, amiodarone,
propafenone, cyclosporin, macrolide
antibiotics, and more (all increase digoxin
serum concentrations).
– cholestyramine and antacids: reduce digoxin
absorption.
