Drugs Used in Cardiac Failure

Chronic heart failure (CHF) is a condition that affects 1.5-2% of Australians, where the heart is unable to maintain a strong enough blood flow and is characterised by an underlying structural abnormality or cardiac dysfunction that impairs the ability of the ventricles of the heart to fill with, or eject, blood. Shortness of breath on exertion is one of the most common symptoms, which may also include fluid retention, paroxysmal nocturnal dyspnoea, palpitations, syncope, orthopnoea, dry irritating cough and fatigue.

Risk factors for CHF include;

• Common
• Coronary heart disease and prior myocardial infarction
• Hypertension, and
• Diabetes.

• Less common causes
• Non-ischaemic idiopathic dilated cardiomyopathy (familial).

• Uncommon causes
• Valvular heart disease
• Non-ishcaemic dilated cardiomyopathy (due to long term alcohol abuse)
• Chronic arrhythmia
• Drug-induced cardiomyopathy (particularly with chemotherapy drugs such as doxorubicin, daunorubicin, cyclophosphamide, paclitaxel and mitoxantrone), and
• Hypertrophic cardiomyopathy (familial).

Physical examinations are important for initial diagnosis, however clinical symptoms are often unreliable, and it is important to perform additional investigations as confirmation. As a minimum, investigations include electrocardiogram (ECG), chest x-ray, echocardiogram and blood tests.

Non-pharmacological management may be as important as prescribing appropriate medications. Regular physical activity has been shown to reduce physical deconditioning and help improve functional capacity and symptoms. Reduction of sodium intake is recommended to prevent fluid overload. Fluid management is a key measure in symptom monitoring and control for many patients. Alcohol is a direct myocardial toxin and may impair cardiac contractility. Smoking cessation is important as tobacco smoke is atherogenic, reduces the oxygen content in blood as well as provoking vasoconstriction.

There is increasing evidence to support use of combination pharmacological therapy to improve prognosis and control signs and symptoms. It is important to start with low doses and then gradually up-titrate to the optimal dose over several months. If symptomatic hypotension develops on combination therapy, the dose of angiotensin converting enzyme inhibitor (ACEI) and diuretic should be reduced before reducing the dose of beta blocker.

Angiotensin Converting Enzyme Inhibitor

Because of the major importance of activation of the renin-angiotensin-aldosterone system in CHF progression, the use of ACEIs in blocking this pathway is seen as a cornerstone of successful therapy. ACEIs have been shown to improve symptoms, reduce the risk of CHF-related hospitalisation and prolong survival. ACEIs are first-line treatment for all classes of CHF, where therapy should begin with a low dose, then up-titrate slowly.

Common adverse effects: Hypotension, dizziness, hyperkalaemia, cough, renal impairment, angioedema (rare).

Angiotensin II Receptor Blockers (ARB)

Patients unable to tolerate ACEIs due to side effects such as cough or skin rashes, should be offered an ARB. Studies comparing the use of ACEIs and ARBs in CHF show similar outcomes. If a patient had angioedema whilst on an ACEI, there is possible cross-reactivity and a harm-benefit analysis is required prior to initiating therapy.

Common adverse effects: Dizziness, hypotension, hyperkalaemia.

Beta Blockers

Beta blockers inhibit the effects of chronic activation of the sympathetic nervous system acting on the myocardium. Bisoprolol, carvedilol and metoprolol succinate improve symptom control, prolong survival, reduce hospitalisations and mortality. Nebivilol is approved for use in the treatment of stable heart failure in patients above 70 years old.

Beta blockers are recommended for all CHF patients (including older patients and patients with peripheral vascular disease [without critical limb ischaemia], diabetes and chronic obstructive airway disease). Those on a beta blocker for other comorbidities (i.e. angina, hypertension) should be switched to a heart failure specific beta blocker.

Beta blockers may aggravate heart failure and cause symptomatic hypotension during initiation of therapy. These effects can be minimised by beginning at a low dose, and slowly titrating up. They should not be initiated during acute decompensation, but after the patient has stabilised.

Common adverse effects: Bradycardia, hypotension, dizziness, bronchospasm, cold extremities, insomnia, nightmares.

Diuretics

Diuretics increase urine sodium excretion and reduce fluid retention, providing rapid symptom improvement. Loop diuretics are the diuretics of choice in CHF, although they are commonly used with thiazide diuretics in clinical practice. Chronic diuretic therapy has not been shown to improve survival and should only be reserved for symptom control.

Common adverse effects: Hyponatraemia, hypokalaemia, hypomagnesaemia, dehydration, hyperuricaemia, gout, dizziness, orthostatic hypotension, syncope.

Aldosterone Antagonists

Aldosterone receptors within the heart can mediate fibrosis and hypertrophy, and blocking them with aldosterone antagonists may provide benefit. When added to existing treatment, eplerenone and spironolactone have been shown to improve symptoms and reduce the risk of death.

Aldosterone antagonists increase the risk of hyperkalaemia, particularly in the presence of ACEI/ARB and/or renal impairment. Spironolactone is also an androgen receptor antagonist, and may cause feminisation side effects.

Common adverse effects: Hyperkalaemia, hyponatraemia (spironolactone), hypotension, dizziness, endocrine effects (spironolactone) – gynaecomastia, menstrual abnormalities, sexual dysfunction.

Digoxin

The cardiac glycoside, digoxin, inhibits sodium-potassium adenosine triphosphatase, to improve inotropic responsiveness in CHF patients. Digoxin has been shown to reduce CHF-related hospitalisations but not mortality.

Digoxin may be considered in patients with sinus rhythm who have not responded to the first-line therapies above, and also in patients who have atrial fibrillation and poor rate control. The half-life of digoxin may be significantly prolonged with renal impairment, so the maintenance dose may be lower and plasma monitoring may be required.

Common adverse effects: Nausea and vomiting, visual disturbances (i.e. blurred vision), bradycardia, dizziness, anorexia.

Ivabrabine

Ivabradine is a direct sinus node inhibitor and slows heart rate. It can be used in patients with CHF who are in sinus rhythm and are intolerant of beta blockers, or have poor rate control despite taking the maximum tolerable beta blocker dose. When added to other therapies, it may reduce CHF-related hospitalisations. Ivabradine is absorbed best when taken with food. It is hepatically cleared, thus caution needs to be exercised when taken concurrently with cytochrome P3A4 inhibitors (i.e. clarithromycin, itraconazole, ketoconazole).

Common adverse effects: Transient areas of enhanced brightness in the visual field, especially in the first two months of treatment, bradycardia (dose-related), dizziness.

Drugs to avoid in CHF include;

• Anti-arrhythmic agents (except beta blockers and amiodarone)
• Verapamil, diltiazem (in most cases)
• Tricyclic antidepressants
• Nonsteroidal anti-inflammatories and COX-2 Inhibitors
• Pioglitazone, rosiglitazone
• Corticosteroids
• Moxonidine (has been associated with increased mortality in CHF patients)
• Trastuzumab (has been associated with the development of reduced Left Ventricular Ejection Fraction and CHF), and
• Preparations with high sodium load (i.e. many soluble preparations, including soluble Panadol, Ural, Berocca).