Management of Congestive Cardiac Failure

MBChB IV MPYA040

Dr. A.S.R Mmekoa

Department of Pharmacology and Therapeutics
Sefako Makgatho Health Sciences University
Room N513, BMS
Email: alpheus.mmekoa@smu.ac.za
Management of Congestive Cardiac Failure

At the end of the lecture, the student must be able to discuss the drugs for the treatment congestive cardiac failure under the following headings:

1. Drug classification and sub-classification if any

2. Indications
3. Mechanism of action
4. Pharmacokinetics
5. Contraindications
6. Cautions
7. Adverse reactions

8. Special prescriber’s points

Management of Congestive Cardiac Failure

Heart Failure

- a clinical syndrome in which an abnormality of cardiac function causes an inability of the heart to meet the requirements of the metabolizing tissues.

Patients have the following features:

• Symptoms typical of heart failure :(Breathlessness at rest or on exercise, fatigue, tiredness, ankle swelling)

• Signs typical of heart failure: Tachycardia, tachypnea, pulmonary rales, pleural effusion, raised jugular venous pressure, peripheral edema, hepatomegaly
and
• Objective evidence of a structural or functional abnormality of the heart at rest (cardiomegaly, third heart sound, cardiac murmurs, abnormality of the
echocardiogram, raised natriuretic peptide concentration)

• Heart failure was one of the first diseases for which guidelines described specific therapies for each stage of the disease.

Classification of the stages of heart failure was that of the NYHA, a classification still in use:
class I (left ventricular dysfunction, no symptoms);
class II (symptoms at medium-to-high levels of physical exercise);
class III (symptoms at low levels of physical exercise); and

class IV (symptoms at rest or daily life physical activities such as brushing teeth).
 Management of Congestive Cardiac Failure

Comparison of ACCF/AHA Stages of HF and NYHA Functional Classifications

ACCF/AHA stages of HF NYHA functional classification
Stage A At high risk for HF but without structural heart disease or None
symptoms of HF
Stage B Structural heart disease but without signs or symptoms of HF Class I No limitation of physical activity. Ordinary physical activity does not cause
symptoms of HF.
Stage C Structural heart disease with prior or current symptoms of HF Class I No limitation of physical activity. Ordinary physical activity does not cause
symptoms of HF.
Class II Slight limitation of physical activity. Comfortable at rest, but ordinary
physical activity results in symptoms of HF.
Class III Marked limitation of physical activity. Comfortable at rest, but less than
ordinary activity causes symptoms of HF.
Class IV Unable to carry on any physical activity without symptoms of HF, or
symptoms of HF at rest.
Stage D Refractory HF requiring specialized interventions Class IV Unable to carry on any physical activity without symptoms of HF, or
symptoms of HF at rest.
https://www.uptodate.com/contents/image?imageKey=CARD%2F120580

Prevention and Treatment

• Ischemic heart disease, hypertension, and valvular diseases are the most prevalent causes of heart failure.
• People at high risk (stage A) should therefore be consequently treated with drugs with an established effect on the natural course of these diseases, in
conjunction with appropriate lifestyle changes.
• Studies in thousands of patients have reproducibly shown that blood pressure lowering in hypertensive patients and lipid- lowering with statins in
dyslipidemic patients reduce not only the incidence of myocardial infarction and death but also the incidence of heart failure.
Management of Congestive Cardiac Failure

Figure 29–3 AHA/ACC 2013 Heart Failure Treatment Guidelines: stages in the development of HF and recommended therapy by stage. (See Yancy et al.,
2013 and 2016, for details.)
 Management of Congestive Cardiac Failure

HEART FAILURE MANAGEMENT PRINCIPLES

• Identification of patients at risk and institution of appropriate therapeutic and preventive measures

• Identification of relevant symptoms and clinical features that lead to a diagnosis and institution of basic, standard treatment
where appropriate.

• Once the diagnosis is confirmed, initiate treatment promptly and do further investigations to rule out reversible causes of LV
dysfunction.

• To make patients to feel better: relief symptoms

• To reduce hospitalization (new and recurrent).

• Ability to detect complications in those being followed up

• To prolong survival/improve life expectancy: retard or delay progression to heart failure

NB!!! LIFE STYLE MODIFICATION ONCE THE PATIENT IS STABLE INCLUDING ANNUAL INFLUENZA AND
PNEUMOCOCCAL VACCINATIONS

see lecture notes on the Management of Hypertension

 Management of Congestive Cardiac Failure

PHARMACOLOGICAL THERAPIES CLASSIFICATION OF DRUGS:

1. Reduction of preload
i. Diuretics
ii. Nitrates

2. Reduction of afterload
i. Direct vasodilators: Hydralazine

3. Reduction of preload and afterload

• ACEIs
• ARB
• ARNI: Sacubitril/valsartan
• β-Blockers
• HCN Channel Blocker: Ivabradine
• Aldosterone antagonists: Spironolactone, Eplerenone

4. Positiveinotropic
Digoxin, Levosimendan (not in SA)

5. Others (acute HF)

i. Phosphodiesterase inhibitors
ii. β-Adrenergic agonist: Dobutamine, Dopamine
iii. Bipiridines: Milrinone

see lecture notes on the Management of Hypertension

Management of Congestive Cardiac Failure

Order of Therapy

Figure 18.11 Treatment options for various stages of HF. ACE = angiotensin-converting enzyme; ARBs = angiotensin receptor blockers; FDC = fixed-dose
combination; HYD = hydralazine; ISDN = isosorbide dinitrate. Stage D (refractory symptoms requiring special interventions) is not shown.
 Management of Congestive Cardiac Failure

Inhibitors of the Renin–Angiotensin–Aldosterone System

The compensatory activation of the RAAS in HF leads to increased workload on the heart and a resultant decline in cardiac function.
Therefore, inhibition of the RAAS is an important pharmacological target in the management of HF.

Reduces the work of the heart by decrease preload and afterload

A. ACEIs in CHF
i. Reduction of afterload by reduction of the formation of angiotensin II (present in high concentration in CHF) without reflex
tachycardia
ii. Reduction of preload by reduction of the formation of aldosterone and water and salt
iii. Decrease sympathetic drive,
iv. Prevention of ventricular remodeling
v. In pts with left ventricle systolic dysfunction
vi. In pts with low ejection fraction
Used at all stages of HF
Reduces long term mortality

Figure 18.5 Effects of ACE inhibitors. [Note: The reduced retention of sodium and water results
from two causes: decreased production of angiotensin II and aldosterone.]

see lecture notes on the Management of Hypertension

 Management of Congestive Cardiac Failure
ACEIs should be used in HF patients who do not have symptoms reduce the risk of disease progression and improve patient survival.
- In patients with fluid retention ACEI’s are typically combined with diuretics.
-Patients who cannot tolerate ACEI’s should be treated with angiotensin II receptor blockers (ARBs).
-Other "vasodilators" such as a combination of hydralazine plus nitrate therapy may be used if patients cannot tolerate both ACEI’s and ARBs
-Combination of an ACE Inhibitor and ARB not used diabetes, stroke, heart failure, myocardial infarction, or chronic kidney disease.

Figure 16.10 Effects of various drug classes on the renin–angiotensin–aldosterone system. Blue = drug target enzymes; red = drug class. Lippincott p 210

Mechanism of action
-Inhibition of conversion of angiotensin I to angiotensin II, leading to suppressed aldosterone secretion and decreased water and Na+ retention. This decreases
PVR
-Inhibits inactivation of bradykinin, leading to vasodilation (bradykinin, a potent vasodilator that works by stimulating release of nitric oxide and prostacyclin).
-Direct stimulation of the production of renal and endothelial vasodilatory prostaglandins stimulate vasodilatation
Indications
i. Hypertension
ii. ii. Congestive cardiac failure;
see lecture notes on the Management of Hypertension
 Management of Congestive Cardiac Failure
Aldosterone antagonists in congestive cardiac failure
Addition of a low dose of an aldosterone antagonist should be considered in all patients with an LVEF ≤35% and severe symptomatic
HF, i.e. currently NYHA functional class III or IV, in the absence of hyperkalaemia and significant renal dysfunction.
Advantages of Aldosterone antagonists
• Reduction of volume overload and preload
• Reduction of symptoms such as: orthopnoea, paroxysmal nocturnal edema,
• Decrease aldosterone production, water retention and preload.
• Reversal of fibrosis of the myocardium due to high aldosterone level
• Reduced mortality and sudden death
Side effects
i. Hyperkalaemia
ii. Gynecomastia
iii. GIT disturbances: gastritis, peptic ulcer
iv. CNS: Lethargy, confusion
v. Hyperchloremic metabolic acidosis

see lecture notes on the Management of Hypertension

 Management of Congestive Cardiac Failure
β-blockers in CHF
Bisoprolol β 1) carvedilol (α β 1, β 2), metoprolol β 1)
• Decrease heart rate and afterload through vasodilatation (decrease PVR).
• Have protective action of adrenergic nerve stimulation
• Inhibition of the mitogenic activity of catecholamine's and apoptosis
• Decrease oxygen consumption in ischemia and cardiomyopathy.
• Decrease arrhythmias
• Reduce risk of death associated with HF

Which patients should be given a β-blocker?

• LVEF ≤
• Mild to severe symptoms (NYHA functional class II IV);
• Patients should be clinically stable (e.g. no recent change in dose of diuretic).
• Patients with asymptomatic LV systolic dysfunction after MI
• Optimal dose level of an ACEI or/and ARB (and aldosterone antagonist, if indicated).
• May temporarily worsen symptoms but result in long term improvement in heart function

see lecture notes on the Management of Hypertension

 Management of Congestive Cardiac Failure
Carvedilol
• Should be introduced cautiously in patients with cardiac failure who are haemodynamically stable and already controlled on diuretics
and ACE inhibitors!
• Usual dose 6.25 mg bd Initially 3.125 mg bd and then titrate 3.125 mg bd 2 weeks, → 6.25 mg bd → 12.5 mg bd → 25 mg bd (max) if
necessary.
• Patients require careful monitoring during titration. Treatment needs to be initiated slowly under medical supervision
• Visits every 2 4 weeks to up titrate
• Do not increase dose if signs of worsening HF, symptomatic hypotension (e.g. dizziness) or excessive bradycardia (pulse rate <50/min at
each visit.
• Use with caution in patients receiving digoxin, since both digoxin and carvedilol slow AVconduction
• Worsening of cardiac failure or fluid retention may occur during up titration of carvedilol.
• Diuretics should be increased and the carvedilol dose should not be advanced until clinically stable.
• Occasionally it may be necessary to reduce the carvedilol dose or temporarily discontinue it.
• If carvedilol is discontinued for more than 2 weeks, therapy should be recommenced at 3.125 mg twice daily and increased gradually as
below.
• Contact lens wearers should be advised of the possibility of reduced lacrimation.

see lecture notes on the Management of Hypertension

 Management of Congestive Cardiac Failure
Carvedilol
Side effects
• Asthmatic attacks
• Induction of heart failure
• Bradycardia
• Arrhythmias
• CNS fatigue, depression, sleep disturbances
• GIT disturbances
• Hypoglycemia with IDDM
• Raynaud's phenomenon
• Sexual dysfunction
Contraindication
Absolute
• Asthma
• Second and third degree heart block
• Bradycardia
Relative:
• IDDM
• Chronic occlusive arterial disease
• Chronic lung disease
• Raynaud's syndrome
• Pregnancy
NB: Beta blocker should be discontinued slowly because it can cause withdrawal syndrome (rebound worsening of angina,
myocardial infarction, tachycardia)

see lecture notes on the Management of Hypertension

 Management of Congestive Cardiac Failure
Diuretics
• Diuretics provide relief from the symptoms and signs of pulmonary and systemic venous congestion in patients with HF.
• Diuretics cause activation of the renin angiotensin aldosterone system in patients with mild symptoms of HF and should
usually be used in combination with an ACEI/ARB.
• In general, a loop diuretic will be required in moderate or severe HF.
• A thiazide may be used in combination with loop diuretics for resistant oedema, but with caution to avoid dehydration,
hypovolaemia, hyponatraemia or hypokalaemia
• It is essential to monitor potassium, sodium and creatinine levels during diuretic therapy.
Thiazide Diuretics: see lecture notes on the Management of Hypertension

see lecture notes on the Management of Hypertension

 Management of Congestive Cardiac Failure
Digitalis in CHF
• Useful especially in systolic dysfunction
• In patients with symptomatic HF and AF, digoxin may be used to slow a rapid ventricular rate. In patients with AF and an LVEF ≤40% it
should be used to control heart rate in addition to, or prior to a β blocker
• Does not prolonged life expectancy
• Should be reserved for patients who still have symptoms of HF after being treated with an ACEI, diuretic, and a / β blocker
• Patients taking both diuretics and digitalis may need supplementation of potassium.
• Digoxin is of no value in patients with sinus rhythm hypertrophic cardiomyopathy, myocarditis, mitral stenosis, chronic constructive
pericarditis and diastolic HF
Digoxin Contraindications
i. Second or third degree heart block (without a permanent pacemaker); caution if suspected sick sinus syndrome
ii. Pre excitation syndromes
iii. Previous evidence of digoxin intolerance

• Starting dose: loading doses of digoxin are generally not required in stable patients with sinus rhythm.
• A single daily maintenance dose of 0.25 mg is commonly employed in adults with normal renal function.
• In the elderly and in those with renal impairment, a reduced dose of 0.125 or 0.0625 mg o.d . should be used.
• The digoxin concentration should be checked early during chronic therapy in those with normal renal function.
• The therapeutic serum concentration should be between 0.6 and 1,2 ng/mL, lower than previously recommended
Management of Congestive Cardiac Failure
 Management of Congestive Cardiac Failure

Adverse effects of digoxin

NB: Narrow margin between effective therapeutic and
toxic doses. 3. Neurological effects
1. Effects on the heart -Headache
Mild to moderate: -Fatigue
-Ventricular ectopic beats -Neuralgic pain (usually trigeminal neuralgia)
-Bradycardia -Mental confusion
Severe: -Disorientation
-Ventricular tachycardia or fibrillation -Paraesthesia
-SA or AV block 4. Vision
2. GIT effects -Blurred vision with white borders
-Anorexia -Chromatopsia for yellow and green ( a disturbance of vision in which
-Nausea and vomiting. colourless objects appear coloured).

-Diarrhoea -Diplopia

-Abdominal pain 5. Others

-Gynecomastia
- Galactorrhoea(peripheral estrogenic action and stimulation of
hypothalamus)
 Management of Congestive Cardiac Failure
Digoxin Special Prescriber points:
• A careful risk benefit assessment is necessary before prescribing digoxin with regular review during maintenance therapy to avoid serious toxicity and
d/I

• Dose should be individualised and factors such as cardiac status, age, lean body mass, electrolytes, renal function, plasma level, concurrent drugs,
clinical response taken into account

• Pt’s should be aware of the signs of toxicity and report them early

• Therapeutic serum level should be monitored and blood samples should be collected at least 6 8 hours after the last dose

• In HF with atrial fibrillation digoxin is beneficial in controlling the ventricular rate

• In patients with CHF and no atrial fibrillation the benefits is controversial

Drug interactions
• Drugs that may increase serum concentrations of digoxin increase the risk of AV nodal block and sinus bradycardia: quinidine, amiodarone,
verapamil, diltiazem, spironolactone, chloroquine, trimethoprim, simvastatin, potassium sparing diuretics, β-blockers, verapamil, diltiazem > Reduce
digoxin requirements to half the usual dose.

Verapamil, diltiazem and B-blockers: additive depressant on AV nodal block and increased risk of heart block and sinus bradycardia.
Potassium-sparing diuretics: e.g., spironolactone: digoxin concetrations increased by up to 20%.
Drugs that may potentiate digoxin toxicity by causing potassium depletion and other electrolyte disturbances: Certain diuretics, amphotericin B,
corticosteroids
 Management of Congestive Cardiac Failure
Ivabradine in Congestive Cardiac Failure
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker
• The hyperpolarization-activated cyclic nucleotide–gated (HCN) channel is responsible for the If current and setting the pace within the SA node.
• Inhibition of the HCN channel results in slowing of depolarization and a lower heart rate (Figure 18.7).
• Reduction in heart rate is use and dose dependent.

Mechanism of action
A selective inhibitor of the If ion channel found in cardiac
pacemaker cells of the sinoatrial node.
• Reduces heart rate at rest and during exercise in
patients in sinus rhythm while maintaining myocardial
contractility and atrioventricular conduction (it does
not slow the ventricular rate in AF

Figure 18.7 Effects of inhibition of If current with ivabradine. HR = heart rate; K+ = potassium; Na+ = sodium; SA
= sinoatrial.
 Management of Congestive Cardiac Failure
Ivabradine Pharmacokinetics
Should be administered with meals to increase absorption; it undergoes extensive first pass metabolism by cytochrome P450 3A4 to an active metabolite, which
is also a 3A4 substrate. Ivabradine has a high volume of distribution and is 70% protein bound with half-life is 6 hours, which allows for twice daily dosing.
Ivabradine indications
• Chronic heart failure for people: NYHA class II to IV with systolic dysfunction and who are in sinus rhythm with a heart rate of >75 beats per minute.

• In combination with standard therapy including beta blocker therapy, angiotensin converting enzyme (ACE) inhibitors and aldosterone antagonists;

• When beta blocker therapy is contraindicated or not tolerated and with a left ventricular ejection fraction of 35% or less.

• Should only be initiated after a stabilisation period of 4 weeks on optimized standard therapy with ACE inhibitors, beta blockers and aldosterone
antagonists.

• The concomitant use of verapamil or diltiazem is contraindicated

• No benefits on cardiovascular outcome only to alleviate the symptoms;

• ECG monitoring and HR monitoring necessary (increased risk of developing atrial fibrillation)

• Titrate to optimal dose

❖ Should be initiated by a heart failure specialist with access to a multidisciplinary heart failure team.
 Management of Congestive Cardiac Failure

Ivabradine Adverse effects

i. Bradycardia
ii. Inhibits similar channels in the eye, and luminous phenomena (enhanced brightness) may occur
early in therapy. This may be ameliorated by dose reduction.
C/I
i. Pregnancy or breast feeding,
ii. Advanced heart block,
iii. With potent 3A4 inhibitors.
 Management of Congestive Cardiac Failure

ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI)

• Neprilysin is the enzyme that breaks down vasoactive peptides such as angiotensin I and II, bradykinin, and natriuretic
peptides.
Inhibition of neprilysin augments the activity of these vasoactive peptides.

Figure 18.6 Effects of angiotensin receptor blocker–neprilysin inhibitors. ARB = angiotensin receptor blocker; ARNI =
angiotensin receptor neprilysin inhibitor; AT1 = angiotensin type 1; NI, neprilysin inhibitor; NP = natriuretic peptide; RAAS =
renin– angiotensin–aldosterone system; SNS = sympathetic nervous system. Lippincott's p239
 Management of Congestive Cardiac Failure

A. Sacubitril/valsartan
Sacubitril/valsartan is the first available angiotensin receptor–neprilysin inhibitor (ARNI).
Mechanism of action
⎯ Sacubitril inhibits neprilysin, thus reducing breakdown of ANP and BNP;
⎯ valsartan inhibits action of angiotensin II on its receptors, prevent remodeling
(Inhibition of neprilysin results in increased concentration of vasoactive peptides, leading to natriuresis, diuresis, vasodilation, and inhibition of
fibrosis.
• Together, the combination decreases afterload, preload, and myocardial fibrosis.
An ARNI improves survival and clinical signs and symptoms of HF, as compared to therapy with an ACE inhibitor.
Indications
• ARNI should replace an ACE inhibitor or ARB in HFrEF in patients who remain symptomatic on optimal doses of a β-blocker and an ACE inhibitor
or ARB.
Adverse effects
• The adverse effect profile is similar to that of an ACE inhibitor or ARB. Because of the added reduction of afterload, hypotension is
more common with an ARNI.
• Due to inhibition of neprilysin with sacubitril, bradykinin levels may increase and angioedema may occur. Therefore, the combination
is contraindicated in patients with a history of hereditary angioedema or angioedema associated with an ACE inhibitor or ARB.
• To minimize risk of angioedema, an ACE inhibitor must be stopped at least 36 hours prior to starting sacubitril/valsartan.
 Management of Congestive Cardiac Failure
Hydralazine and Isosorbide dinitrate (H ISDN )

Hydralazine- vasodilator; reduces blood pressure acting directly on arterial smooth muscle to cause vasodilation and a ↓in total PVR.
Isosorbide dinitrate- also a vasodilator; used to relieve angina; it is longer acting but of slower onset than nitroglycerin and may provide prophylaxis
against angina for several hours.
• In symptomatic patients with an LVEF ≤40% the combination of H-ISDN may be used as an alternative if there is intolerance to both an ACEI and
an ARB.
• Adding the combination of H-ISDN should be considered in patients with persistent symptoms despite treatment with an ACEI, β blocker and an
ARB or aldosterone antagonist. Treatment with H-ISDN in these patients may reduce the risk of death

Advantages of Nitrates in CHF:

i. Decrease preload - Preload is defined as the stretch of myocardium or end-diastolic volume of the ventricles and most frequently refers to the
volume in a ventricle just before the start of systole.
ii. Reduce ventricular filling pressure
iii. Reduce oxygen demand
Contraindications
i. Symptomatic hypotension
ii. Systemic lupus erythematosus - hydralazine is a trigger
iii. Severe renal failure (dose reduction may be needed)
Side effects
• Symptomatic hypotension (e.g. dizziness) often improves with time; consider reducing dose of other hypotensive agents (except
ACEI/ARB/blocker/aldosterone antagonist). Asymptomatic hypotension does not require intervention.
• Arthralgia/muscle aches, joint pain or swelling, pericarditis/pleuritis, rash or fever-consider drug-induced lupus-like syndrome; check ANA
(antinuclear antibodies), discontinue H-ISDN
 Management of Congestive Cardiac Failure

Hydralazine and Isosorbide dinitrate (H ISDN )

Drug interactions
• Other antihypertensive agents: Careful monitoring required to avoid excessive hypotension

• PDE-5 inhibitors (Milrinone) and Nitrates-contraindicated (they both cause nitric oxide release, and PDEE-5
inhibitors do potentiate the hypotensive effect of nitrous oxide = hypotension)

• Heparin + Nitrates –heparin resistance.... due to vasodilation

 Management of Congestive Cardiac Failure
Anticoagulant drugs
Warfarin is not routinely required in patients with HF REF unless they have
• AF (permanent, persistent, or paroxysmal AF without contraindications to anticoagulation)
• LV mural thrombus
• History of systemic or pulmonary emboli, including stroke or transient ischemic attack
• Symptomatic or asymptomatic ischemic cardiomyopathy
• Documented recent large anterior MI or recent MI with documented LV thrombus
Warfarin D/I:
Drugs that enhance anticoagulant effect: Acute alcohol ingestion, allopurinol, amiodarone, anabolic steroids, antibiotics: broad spectrum,
chloramphenicol, metronidazole, macrolides, quinolones, sulphonamides (due to suppression of intestinal flora and inhibition of CYP 450),
antiplatelet, NSAID’s, cimetidine, fibrates, imidazoles, omeprazole, paracetamol, simvastatin, SSRI’s, sulphonylureas, streptokinase,
tamoxifen, testosterone, thyroid hormones, valproate, verapamil, ginko biloba, garlic
Drugs that diminish anticoagulant effect: Chronic alcohol, antiepileptics, nevirapine, oral contraceptives, rifampicin, sucralfate, St John’s
wort & other herbal preparations

Warfarin Special prescriber points:

• The INR should be determined before giving the initial dose, then daily in the early days of treatment, then weakly until maintenance dose is
established, after monthly (goal INR 2.0-3.0 IU)
• If liver, kidney disease, acute illness, bleeding, or suspected D/I monitor more often
• The “alert” bracelet, therapeutic card and list of medications that may alter the response should be issue to the patient
• Patient should be warned not to take any over the counter medicines or herbal remedies without consulting with the doctor
 Management of Congestive Cardiac Failure

Rivaroxaban, dabigatran New oral anticoagulants

Prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation
– Treatment of deep vein thrombosis
– Prevention of recurrent deep vein thrombosis
– Treatment of pulmonary embolism
– Prevention of recurrent pulmonary embolism
– The prevention of venous thrombo-embolism in patients undergoing major orthopaedic surgery of the lower limbs
• No antidote to rivaroxaban
*Idarucizumab is an antidote to dabigatran, Expensive, Humanized antibody fragment
Cardiovascular Journal of Africa: Vol 25 No 2(March/April 2014

Antiplatelet agents
• Antiplatelet agents are not as effective as warfarin in reducing the risk of thromboembolism in patients with AF.
 Management of Congestive Cardiac Failure

1. Whalen, K., Field, C., Radhakrishnan, R., Lippincott’s Illustrated Reviews: Pharmacology, 7th Edition. Philadelphia: Lippincott Williams & Wilkins.

2. South African Medicines Formulary 13th Edition

3. EDL South Africa Hospital Level (Adult) 2019_v2.0

4. Brunton, L et al Goodman and Gilman’s The Pharmacological Basis of Therapeutics 13th Edition;

5. Bertram G. Katzung Basic & Clinical Pharmacology Katzung 14th Edition.

6. Bennett, PN et al Clinical Pharmacology 12th Edition 2012; Sharma

7. New oral anticoagulant: Cardiovascular Journal of Africa: Vol 25 No 2(March/April 2014)

8. Foundation/American Heart Association Task Force on Practice Guidelines, JACC

Management of Congestive Cardiac Failure