Heart Failure Tx

Question 1

Pharmacotherapy of HFrEF

Reduced Ejection Fraction

Answer 1

• 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

Question 2

Diuretics - Mechanism of Action

Answer 2

Reduce preload to improve symptoms
associated with fluid retention.

DO NOT ALTER MORTALITY
ONLY PT PRONE TO SYMPTOM OVERLOAD

loop diuretics most common

Question 3

oop Diuretics

Answer 3

• 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)

Question 4

Furosemide: Dose

considerations

Answer 4

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

Question 5

Furosemide: Dose

Answer 5

• 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.

Question 6

Other Diuretics

Answer 6

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

Question 7

Acutely, much higher doses may be

required due to _____________

Answer 7

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

Question 8

Diuretics - Monitoring

Answer 8

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)

Question 9

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

Answer 9

C. Hypervolemic

JVP > 4
weight increase

Question 10

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

Answer 10

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

Question 11

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

Answer 11

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

Question 12

ACE Inhibitors

pharma nd indications

Answer 12

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

Question 13

ACE Inhibitor

dosing

Answer 13

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

Question 14

ACE Inhibitors
AE
contra

Answer 14

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

Question 15

Angiotensin Receptor
Blockers (ARB)

Pharmacology:

Answer 15

• 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

Question 16

Role of ARB in HFrEF

Answer 16

• 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

Question 17

Angiotensin Receptor
Blockers (ARB)

AE

Answer 17

hypotension, ↑Scr (worsening of renal

function), hyperkalemia

Question 18

Current Status of ARBs in HFrEF

Answer 18

• May represent an alternative in
patients unable to tolerate ACE
inhibitors (mostly due to intolerable
cough)
– Angioedema – cross sensitivity reported

Question 19

b-adrenergic Antagonists
(‘Beta Blockers’)

pharm
indications

Answer 19

• 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

Question 20

Beta Blockers

what are the 3 types
which ones can be used?

Answer 20

• 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

Question 21

Beta BlockersAE

Answer 21

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)

Question 22

BB

Contraindications

Answer 22

– 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)

Question 23

Carvedilol Or Metoprolol

European Trial: COMET

Answer 23

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

Question 24

Mineralocorticoid Receptor

Antagonists (MRA)

Answer 24

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

Question 25

Spironolactone

dose
ae
contra

Answer 25

• 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

Question 26

Eplerenone

place in therapy

Answer 26

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

Question 27

RALES trial showed?

Answer 27

Hospital admissions for hyperkalemia increase 3x
pt hosptialized for heart failure who received ACEi

In-hospital deaths associated with hyperkalemia increase 3x

Question 28

Reduction of Hyperkalemia

Answer 28

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)

Question 29

Mineralocorticoid Receptor
Antagonists (MRA)
Indications

Answer 29

• 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

Question 30

Hydralazine/Nitrates

Answer 30

• 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…

Question 31

African American Heart Failure Trial

A-HeFT

Answer 31

• 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

Question 32

Hydralazine/Nitrates

Answer 32

• 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

Question 33

Digoxin
add on therapy
pharmacology
indications

Answer 33

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

Question 34

Digoxin
dose
ae

Answer 34

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)

Question 35

Digoxin

contra

Answer 35

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

Question 36

Digoxin
drug interactions (!):

Answer 36

– quinidine, verapamil, amiodarone,
propafenone, cyclosporin, macrolide
antibiotics, and more (all increase digoxin
serum concentrations).
– cholestyramine and antacids: reduce digoxin
absorption.