Treatment of chronic heart failure

At a glance

1. In heart failure with a reduced ejection fraction, four drug classes reduce death and admissions, and together they add years of life: a beta-blocker, an ARNI or ACE inhibitor, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor.
2. All four are started as early as possible and increased every 1 to 2 weeks to the target or the highest tolerated dose. A small rise in creatinine or potassium is expected and is not a reason to stop.
3. Diuretics relieve congestion and prevent admissions but have not been shown to lengthen life, so they are given at the lowest dose that keeps the patient free of fluid.
4. Other drugs are added for chosen patients: ivabradine, digoxin or digitoxin, hydralazine with isosorbide dinitrate, vericiguat and intravenous iron.
5. A defibrillator prevents sudden death when the ejection fraction stays at 35 per cent or less, and resynchronisation helps when there is also a wide QRS with left bundle branch block.
6. With a preserved ejection fraction, an SGLT2 inhibitor and a mineralocorticoid receptor antagonist reduce admissions. The drugs are continued when the ejection fraction recovers.

01Definition and overview

The treatment of chronic heart failure aims to help patients live longer, stay out of hospital, feel better and do more, and to stop the disease progressing. European guidance sorts it into three layers:

• foundational medical therapy, the drugs recommended for every suitable patient because they reduce death and admissions;
• additional medical therapy, drugs that help chosen patients;
• interventional therapy, the devices and procedures: defibrillators, resynchronisation, repair of valves, revascularisation, mechanical support and transplantation.

All of it rests on care that is not a drug: education and self-care, exercise, treatment of the cause and of the other diseases that come with heart failure, and follow-up by a team. What is used depends on the ejection fraction:

Most of the trials behind the reduced group enrolled patients with an ejection fraction of 40 per cent or less (35 per cent or less for devices), so the evidence is strongest there. Current European guidance extends the group to 50 per cent, because patients between 41 and 49 per cent appear to respond to the same drugs.

02Etiology and pathophysiology

What the drugs target

A failing heart switches on the sympathetic nervous system and the renin-angiotensin-aldosterone system. In the short term they hold up the blood pressure and the output; in the long term they retain salt and water, constrict the vessels, and drive the remodelling, fibrosis and arrhythmias that make the heart fail further. The natriuretic peptides, which work against them, are overwhelmed. The foundational drugs block this vicious circle at several points, which is why their benefits add up.

The added drugs act elsewhere: ivabradine slows the sinus node through its funny channel without lowering the pressure; digoxin and digitoxin inhibit the sodium-potassium pump, raising the calcium in the cell and contractility, and slow the atrioventricular node; vericiguat stimulates soluble guanylate cyclase, raising cyclic GMP, which is low in heart failure; and hydralazine dilates the arteries while the nitrate dilates the veins.

03Clinical features

Before each change

Each visit checks the symptoms and NYHA class, the signs of congestion, the weight, the blood pressure (lying and standing) and the heart rate, and the blood tests: creatinine and eGFR, potassium and sodium. The blood tests are repeated 1 to 2 weeks after starting or increasing a drug that acts on the renin-angiotensin system or aldosterone.

Side effects that change the drug

• ACE inhibitors cause a dry cough in about 1 in 10 patients; an ARNI or ARB is used instead.
• Angioedema on an ACE inhibitor rules out an ARNI too, because both raise bradykinin. For the same reason an ARNI is never given with an ACE inhibitor, and the ACE inhibitor is stopped 36 hours before the first dose.
• Spironolactone causes painful gynaecomastia in about 1 in 10 men; eplerenone does not.
• Beta-blockers can briefly worsen fatigue and congestion in the first weeks, which is why they are started at a low dose in a patient without congestion.

04Diagnosis and management

The foundational drugs in reduced ejection fraction

An ARNI works better than an ACE inhibitor: in a large trial, sacubitril/valsartan reduced cardiovascular death or admission for heart failure from about 26.5 to 21.8 per cent compared with enalapril, and death from any cause too. It replaces an ACE inhibitor in patients who still have symptoms, and many patients now start with it. SGLT2 inhibitors reduced the same outcome from about 21 to 16 per cent in patients with or without diabetes, and they are used down to an eGFR of about 20 to 25 mL/min/1.73 m².

Starting them

• All four are started as early as possible, within days to weeks, rather than one after another over months. The order matters less than getting them all on board: the SGLT2 inhibitor and the mineralocorticoid receptor antagonist barely lower the pressure, and the beta-blocker is started once the patient is free of congestion.
• Each is started at a low dose and increased at least every 1 to 2 weeks, guided by symptoms, heart rate, blood pressure and blood tests, to the target dose or the highest dose the patient tolerates. Experts favour a low dose of all four over a full dose of one, although no trial has compared the two approaches; in trials of single drugs, higher doses prevented more events than low doses.
• A mineralocorticoid receptor antagonist is started with caution when the eGFR is below about 30 or the potassium is 5.0 mmol/L or more.
• In hospital, the drugs are started or restarted before discharge and increased quickly afterwards, as described in treatment of acute heart failure.
• Women who may become pregnant are counselled before conception, because ACE inhibitors, ARBs, ARNI, mineralocorticoid receptor antagonists, ivabradine and SGLT2 inhibitors are avoided during pregnancy.

Diuretics

Loop diuretics (furosemide, bumetanide, torasemide) are given for congestion at the lowest dose that keeps the patient free of it, and the dose is reduced when the foundational drugs start to work. Patients learn to adjust the dose themselves with their daily weight. A short course of a thiazide or metolazone can be added for resistant congestion during a decompensation, with close watch on potassium, sodium and kidney function. Long-term use in stable patients is avoided, because it causes severe electrolyte disturbances that can go unnoticed outside hospital.

Additional drugs

The iron trials enrolled patients by an older definition, a ferritin below 100 µg/L, or 100 to 299 µg/L with a transferrin saturation below 20 per cent. The ferritin rises with inflammation and did not reliably identify iron deficiency, so the transferrin saturation alone has replaced it.

Devices and procedures

• Implantable cardioverter-defibrillator (ICD). For secondary prevention, after a cardiac arrest or ventricular tachycardia that caused instability. For primary prevention, when the ejection fraction stays at 35 per cent or less after at least 3 months of full drug treatment, in NYHA class II or III, with a reasonable life expectancy in good health. The evidence is strongest in ischaemic heart disease. In non-ischaemic cardiomyopathy, a large trial found fewer sudden deaths but no clear fall in overall deaths; pooled with older trials, defibrillators do lower mortality, so an ICD should be considered, and the decision is individual and favours younger patients. A primary-prevention ICD is not implanted within 40 days of a myocardial infarction, when it does not reduce deaths. It is not offered in NYHA class IV unless resynchronisation, an assist device or transplantation is planned, and switching it off is discussed at the end of life.
• Cardiac resynchronisation therapy (CRT) paces both ventricles to restore their coordination. It is recommended for symptomatic patients in sinus rhythm with an ejection fraction of 35 per cent or less despite full drug treatment and a QRS of 150 ms or more with left bundle branch block. It is considered with a QRS of 130 to 149 ms with left bundle branch block, or 150 ms or more without it, and it is not used with a QRS below 130 ms. CRT rather than right ventricular pacing alone should be considered in patients with a reduced ejection fraction who need ventricular pacing for heart block, and an upgrade to CRT when frequent right ventricular pacing has left the ejection fraction at 35 per cent or less. With a wide QRS and left bundle branch block, where the drugs are less likely to restore the ejection fraction, CRT may be planned alongside the drugs, but the ejection fraction is measured again before implantation. Whether the device also defibrillates (CRT-D) or only paces (CRT-P) is decided for each patient; CRT-P is common in older patients and in non-ischaemic disease.
• Revascularisation: coronary bypass surgery for multivessel disease improved long-term survival in suitable patients with ischaemic cardiomyopathy, while stenting did not reduce deaths or admissions in a trial, though it treats angina.
• Valves: transcatheter repair for severe secondary mitral regurgitation that persists despite full drug treatment and CRT, in patients who meet the criteria (see mitral regurgitation), and replacement of a stenotic aortic valve.
• Atrial fibrillation: a beta-blocker for rate control, anticoagulation by the stroke risk, and catheter ablation in selected patients, which can improve symptoms and the ejection fraction. When the rate cannot be controlled, the atrioventricular node can be ablated and CRT implanted.

Preserved ejection fraction

• An SGLT2 inhibitor and a mineralocorticoid receptor antagonist for every patient with symptoms. SGLT2 inhibitors reduced cardiovascular death or admission by about a fifth in two large trials, mostly by preventing admissions. Finerenone, a non-steroidal antagonist, reduced the combination of worsening heart failure events and cardiovascular death in patients with an ejection fraction of 40 per cent or more; spironolactone is the steroidal alternative.
• Diuretics for congestion.
• Semaglutide or tirzepatide for patients with obesity (a body mass index of 30 or more) and an ejection fraction of 45 per cent or more: they reduce weight, improve symptoms and exercise capacity, and may reduce heart failure events.
• An ARNI, ACE inhibitor or ARB may be considered; their benefit was small and uncertain.
• Treatment of the cause and of what makes it worse: blood pressure, atrial fibrillation, coronary disease, diabetes, kidney disease, sleep apnoea, and specific treatments such as tafamidis for transthyretin amyloidosis (see cardiomyopathies).

Improved ejection fraction

A patient whose ejection fraction has recovered continues the foundational drugs at the doses that achieved it. In a small trial of patients with recovered dilated cardiomyopathy, 11 of 25 who stopped their drugs relapsed within six months, and none of those who continued. Slow withdrawal is considered only exceptionally, at the patient's request, in highly selected patients whose heart failure had a clear reversible cause, with full recovery of the heart and normal natriuretic peptides, and with close follow-up.

Advanced heart failure

When symptoms, admissions and organ damage persist despite full treatment, the patient is referred early to an advanced heart failure centre:

• Heart transplantation, the best treatment for suitable patients, limited by donor hearts. With careful selection, about 80 to 90 per cent survive the first year, and median survival is about 12 years. Pulmonary vascular resistance that stays high despite vasodilators, and active cancer, are contraindications. Rejection, infection, cancer and coronary disease of the graft are the long-term risks.
• A durable left ventricular assist device, as a bridge to transplantation or as permanent treatment for patients who cannot have one.
• Palliative care, alongside or instead of these: control of breathlessness, pain and anxiety, advance care planning, and a discussion of switching off the defibrillator.

Self-care and the rest of care

• Education of the patient and the family: what the drugs do, daily weights, and acting on a weight gain of more than 2 kg in 3 days by contacting the team or increasing the diuretic.
• Salt moderation, avoiding more than about 5 g of salt a day; a stricter limit did not reduce events in a trial. Routine fluid restriction is not advised in chronic heart failure; it may be used for a while in a patient with a low sodium.
• Exercise training and cardiac rehabilitation for every stable patient: better exercise capacity and quality of life, and fewer admissions.
• Vaccination against influenza, pneumococcus and COVID-19; stopping smoking; little or no alcohol, and none in alcoholic cardiomyopathy.
• A review of all drugs at each visit, removing those that worsen heart failure (listed in chronic heart failure).
• Follow-up by a heart failure team, with a specialist nurse, a pharmacist and the general practitioner, and remote monitoring for some patients.

05Epidemiology

The treatment that works is underused. In a large American registry of outpatients with a reduced ejection fraction, about a third of eligible patients took no beta-blocker, two thirds no mineralocorticoid receptor antagonist, and 1 per cent took target doses of all the neurohormonal drugs together. Older age, low blood pressure, kidney disease, worse symptoms and a recent admission all made full treatment less likely. These are the patients at highest risk, who have the most to gain.

06Prognosis

Treatment has transformed the outlook of heart failure with a reduced ejection fraction. Combining the four foundational drugs, compared with an ACE inhibitor and a beta-blocker alone, was estimated to reduce cardiovascular death or admission by about 60 per cent and death from any cause by almost half. For a patient aged 55, that means about 8 more years free of these events and about 6 more years of life; for a patient aged 80, about 2.7 and 1.4 years. These figures come from comparing trials, not from one trial of the combination, so they are an estimate.

Each layer adds to this. Defibrillators prevent sudden death, which now causes a smaller share of deaths than before, and resynchronisation reduces symptoms, admissions and deaths in patients with a wide QRS. Many patients recover part or all of their ejection fraction, and they do best while the drugs are continued. In preserved ejection fraction, treatment reduces admissions and improves symptoms, but no drug has clearly reduced deaths. A larger share of these patients die of non-cardiovascular causes than with a reduced ejection fraction, about a third to a half, and only a minority die of heart failure itself. Without treatment, or on low doses of too few drugs, the poor outlook described in chronic heart failure remains.

Check yourselfAnswer, then say how sure you were: a lucky guess still counts as a weak point.

1Which drugs form the foundational treatment of heart failure with a reduced ejection fraction?

Furosemide, digoxin, aspirin and a statinIvabradine, hydralazine, isosorbide dinitrate and vericiguatA beta-blocker, an ARNI or ACE inhibitor, a mineralocorticoid receptor antagonist and an SGLT2 inhibitorAmlodipine, a thiazide, an ACE inhibitor and spironolactone

2Two weeks after ramipril is increased, a patient's creatinine has risen from 100 to 125 µmol/L and the potassium is 5.2 mmol/L. He feels well. What is the right next step?

Continue the dose and recheck the blood tests in 1 to 2 weeksStop ramipril for goodStop ramipril and start an ARB insteadHalve the dose of every heart failure drug

3Which patient should be offered cardiac resynchronisation therapy?

A patient with an ejection fraction of 45 per cent and a QRS of 100 msA patient with an ejection fraction of 30 per cent, atrial fibrillation and a narrow QRSA patient in NYHA class I with an ejection fraction of 50 per cent and right bundle branch blockA patient in sinus rhythm with an ejection fraction of 30 per cent, left bundle branch block with a QRS of 160 ms, and symptoms despite three months of full treatment

4A woman's ejection fraction has risen from 30 to 55 per cent after a year of treatment for dilated cardiomyopathy. She feels well and asks to stop her heart failure drugs. What is the best advice?

Stop them all, because the heart has recoveredContinue them, because stopping them led to relapse in almost half of such patients within six months in a trialStop the beta-blocker but keep the othersReplace them all with a diuretic

5In heart failure with a preserved ejection fraction, which drug class has been shown in large trials to reduce admissions for heart failure?

Beta-blockersDigoxinSGLT2 inhibitorsNitrates