Heart of the matter

Congestive cardiac failure is generally referred to as heart failure. I have discussed heart failure in Irish Pharmacist on numerous occasions since 2020 and previously I discussed causes, prognosis, types, symptoms, diagnosis, non-pharmacological options as well as options like surgery and pacemakers for heart failure control. For this article, I will concentrate solely on the pharmacological treatment options for what is a condition when the heart is not working adequately. It cannot meet the body’s need for blood because it is not pumping properly, and this usually occurs because the heart muscle has become too weak or stiff to work properly.

Medication

The aim of medication is to improve symptoms of heart failure and prevent further damage to the heart.

The main combination of medicines for heart failure includes:

• A diuretic;

• An angiotensin-converting enzyme (ACE) inhibitor;

• A beta-blocker;

• An aldosterone antagonist;

• Ivabradine;

• Sacubitril valsartan.

Diuretics

Diuretics result in a rapid improvement in symptoms and increased exercise tolerance in more than two-thirds of patients.5 Diuretics help to relieve ankle swelling and breathlessness caused by heart failure. They work by helping to remove water and salt from the kidneys in the urine. They are not recommended as monotherapy for the treatment of heart failure; it is recommended they be prescribed with an ACE inhibitor or a beta-blocker.6 Loop diuretics are the first choice in heart failure. Loop diuretics include furosemide and bumetanide and there is no difference in efficacy between the different types.5 Thiazide diuretics are less-potent diuretics and are generally only used for mild heart failure or as an add-on therapy,5 ie, bendroflumethiazide.

The dose of diuretic is generally started low and increased slowly until response. People who have heart failure with preserved ejection fraction should usually be offered a low-to-medium dose of loop diuretics (for example, less than 80mg furosemide per day). The dose may be reduced once the patient is started on optimal ACE inhibitor dosage.

Low potassium level is a side effect of diuretics but because they are normally taken with ACE inhibitors for heart failure, this is rarely a problem. NSAIDs should be avoided with diuretics as they reduce their effectiveness, and concomitant use can reduce kidney function.

ACE inhibitors

ACE (angiotensin-converting enzyme) inhibitors block the conversion of the hormone angiotensin I to angiotensin II. Angiotensin II is a natural vasoconstrictor and encourages fluid retention. Thus, ACE inhibitors work by dilating blood vessels, which makes the blood flow more easily and reduces blood pressure. This makes it easier for the heart to pump blood around the body. ACE inhibitors are recommended for mild and severe heart failure. They decrease the rate of hospitalisations, improve symptoms, and increase survival in heart failure patients.7 Examples of ACE inhibitors include ramipril, captopril, enalapril, lisinopril and perindopril. The most common side effect is a dry, irritating cough. They should be started at a low dose and increased every one or two weeks until response. They can cause postural hypotension (dizziness and falls from low blood pressure) when started, so blood pressure should be monitored. Kidney function also needs to be monitored.

Angiotensin receptor blockers (ARBs)

ARBs have been shown to extend life and reduce symptoms in patients with heart failure. They work in a similar way to ACE inhibitors, by widening blood vessels and reducing blood pressure, and tend to be used as an alternative, as they do not usually cause cough. Examples include candesartan, losartan, telmisartan and valsartan. Side effects include hypotension and high potassium levels. Measure serum sodium and potassium, and assess renal function, before and after starting an ARB and after each dose increment.

Beta blockers

Research has shown that beta blockers can reduce symptoms and increase survival in patients with heart failure.8 They are not suitable for asthmatics. They generally are used on patients with little or no fluid retention. They work by slowing the heart rate and perhaps by protecting the organ from the effects of adrenaline and a related chemical, noradrenaline. Dosage should be increased slowly. The beta blockers used to treat heart failure are bisoprolol, carvedilol and nebivolol. These are the only three beta blockers licensed for the treatment of heart failure. Patients who are already taking the drug for a pre-existing condition such as hypertension or angina (ie, atenolol) should be switched to a beta blocker licensed for heart failure once they are diagnosed with heart failure due to left ventricular systolic dysfunction.13 Lethargy and fatigue is the most common side effect of beta blockers. They should not be stopped suddenly, as this can cause a rebound effect with rapid worsening of symptoms. A major trial indicated that nebivolol is more effective than other beta blockers at increasing survival in the over-70s age group.10 However, further studies have questioned the methodology of the SENIORS trial, which indicated that nebivolol is more effective than other beta blockers in controlling heart failure.11 The consensus now is that nebivolol is no more effective than bisoprolol and carvedilol in treating heart failure in the over-70s.

Mineralocorticoid receptor antagonists (MRAs)

MRAs are suitable for some people with heart failure. MRAs are aldosterone antagonists with spironolactone being an example. They work in a similar way to diuretics but can also help heal any scarring of the heart muscle. MRAs are an option in addition to an ACE inhibitor (or ARB) and beta blocker in patients who have heart failure with reduced ejection fraction if they continue to have symptoms of heart failure. Once the target – or maximum tolerated – dose of an MRA is reached, treatment should be monitored monthly for three months and then at least every six months, and at any time the person becomes acutely unwell.

Spironolactone

The most widely used aldosterone antagonist is spironolactone. It is a potassium-sparing diuretic. Regular blood screening to monitor the potassium level is important, as it raises potassium. Raised potassium levels are exacerbated when taken with ACE inhibitors or angiotensin receptor inhibitors. In a two-year review, it reduced mortality in patients with severe heart failure from 46 per cent to 35 per cent when used as an ‘add-on’ therapy to an existing diuretic, ACE inhibitor and beta blockers therapy.9 Side effects of spironolactone include gynaecomastia in men and breast tenderness and increased hair growth in women.

Eplerenone

Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalisation among patients with systolic heart failure and mild symptoms. The most severe side effect of spironolactone, hyperkalaemia, is also observed with eplerenone. While eplerenone is more selective, with the potential for fewer side effects, its overall efficacy has not been proven to be superior to that of spironolactone in clinical trials. Eplerenone can cause hyperkalaemia, sleeping difficulties, dizziness, and headaches.

Digoxin

Digoxin, related to a medicine derived from the foxglove plant, increases the strength of heart muscle contractions, and can also slow down the heart rate. It is recommended for people who have symptoms despite treatment with ACE inhibitors, ARBs, beta blockers, and diuretics. It is used earlier in people who have both heart failure and atrial fibrillation (where the heart is beating irregularly). Potassium levels must be monitored regularly to avoid toxicity due to hypokalaemia. This is especially important when taken with diuretics, which reduce potassium levels.

Anticoagulants

In patients with heart failure in sinus rhythm, anticoagulants should be considered for those with a history of thromboembolism, left ventricular aneurysm, or intracardiac thrombus. Warfarin is the most used anticoagulant and requires careful monitoring.

Antiplatelet medicine

Antiplatelet medicine, for example aspirin 75mg, should be prescribed for patients with the combination of heart failure and atherosclerotic arterial disease (including coronary heart disease). Aspirin is not usually taken with warfarin.

Calcium channel blockers

Amlodipine is a treatment option for co-existing hypertension and/or angina in patients with heart failure, but verapamil, diltiazem or short-acting dihydropyridine agents should be avoided13. The dosage is one tablet daily, preferably in the morning before food.

The most reported adverse reactions with perindopril, indapamide and amlodipine are dizziness, headache, paresthesia, vertigo, somnolence, visual disturbances, tinnitus, palpitations, flushing, hypotension, cough, dyspnea, gastro-intestinal disorders (abdominal pain, constipation, diarrhoea, nausea, dyspepsia, vomiting), pruritus, rash, maculopapular rashes, muscle cramps, ankle swelling, asthenia, oedema, and fatigue.

More specialised pharmacological treatments

Ivabradine

Ivabradine is a useful alternative to beta blockers in patients who cannot tolerate them. It can be used in addition to beta blockers if they are not controlling the heart rate sufficiently.

Ivabradine is recommended in patients with:

• New York Heart Association (NYHA) class II to IV stable chronic heart failure with systolic dysfunction;

• Who are in sinus rhythm with a heart rate of 75 beats per minute (bpm) or more;

• In combination with standard therapy including beta blocker therapy, angiotensin-converting enzyme (ACE) inhibitors and aldosterone antagonists, or when beta blocker therapy is contraindicated or not tolerated;

• With a left ventricular ejection fraction of 35 per cent or less

Ivabradine should only be initiated after a stabilisation period of four weeks on optimised standard therapy with ACE inhibitors, beta blockers and aldosterone antagonists.

Ivabradine should be initiated and monitored by a heart failure specialist.

Sacubitril valsartan

Sacubitril valsartan (Entresto®) was approved by the European Medicines Agency in 2016. It is licensed for symptomatic chronic heart failure with reduced ejection fraction, only in people:

• With New York Heart Association class II to IV symptoms;

• With a left ventricular ejection fraction of 35 per cent or less;

• Who are already taking a stable dose of angiotensin-converting enzyme (ACE) inhibitors or ARBs.

Sacubitril blocks the breakdown of natriuretic peptides produced in the body. Natriuretic peptides cause sodium and water to pass into the urine, thereby reducing the strain on the heart. Natriuretic peptides also reduce blood pressure and protect the heart from developing fibrosis (scar tissues) that occurs in heart failure. Valsartan is an angiotensin receptor blocker, so works by widening blood vessels and reducing blood pressure.

Entresto® is taken twice a day. The recommended starting dose is one tablet of Entresto 49mg/51mg twice a day and the dose then doubled after two to four weeks to 97mg/103mg twice a day. The most common side effects of sacubitril valsartan are hypotension, hyperkalaemia, and renal problems.

Treatment with sacubitril valsartan should be initiated and monitored by a heart failure specialist.

Effectiveness of medication for heart failure with preserved ejection fraction

About half of patients with heart failure in the community have preserved left ventricular ejection fraction (HFPEF). Traditionally, pharmacological research has focused on heart failure with left ventricular systolic dysfunction (LVSD) and found several drugs to be beneficial, including ACE inhibitors, beta blockers, and aldosterone antagonists. However, studies of treatment in patients with preserved left ventricular ejection fraction have found no significant benefit from these drugs. There is some limited evidence that suggests potential benefit of both beta blockers and ACE inhibitors for HFPEF. However, more studies are needed to prove the benefit of these drugs in HFPEF; this means that many patients presenting to pharmacies for these pills to treat heart failure may not be getting any benefit from them.

Disclaimer: Brands mentioned in this article are meant as examples only and not meant as preference to other brands.

Author: Eamonn Brady MPSI (Pharmacist). Whelehans Pharmacies, 38 Pearse St and Clonmore, Mullingar. Tel 04493 34591 (Pearse St) or 04493 10266 (Clonmore). www.whelehans. ie. Eamonn specialises in the supply
of medicines and training needs of nursing homes throughout Ireland. Email ebrady@whelehans.ie