Four Pillars of Heart Failure Therapy and Drugs to Avoid

The four pillars of heart failure therapy are an ARNI (sacubitril/valsartan) or, failing that, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker; a beta blocker; a mineralocorticoid receptor antagonist; and an SGLT2 inhibitor. In heart failure with reduced ejection fraction, all four should be started together, without waiting to complete one before adding the next, and titrated as far as the patient tolerates.

That was the core of the prescribing advice Dr. Rajpal Singh R L, Director Cardiology, Fortis Hospitals, Bannerghatta Road, Bangalore, India, gave to physicians managing heart failure. His teaching follows the ESC (European Society of Cardiology) 2021 heart failure guidelines and the 2023 focused update, combined with the practical adjustments he makes in his own clinic. This article covers why the four drugs are started together, how to prescribe each, the add-on drugs for patients who remain symptomatic, and the drugs that cause harm and must be stopped. The complete guide to heart failure detection and management sets out the overall pathway, and the diagnosis article covers how patients are identified.

Why the four pillars of heart failure therapy start together

The four drugs are started together because each pillar blocks a different part of the neurohormonal cycle that drives heart failure:

"Which one do we start first?" is a question Dr. Singh is always asked. His answer is all four, because they work through different mechanisms. The guidelines say the four can be started simultaneously, in no particular sequence, and should not be delayed. They also favour titrating doses as far as possible before discharge: patients whose medicines are uptitrated aggressively, guided by tolerance and blood pressure, have better outcomes than those whose treatment starts late. Loop diuretics are added purely for symptom relief from congestion.

Dr. Singh also stressed continuity. The four drugs are meant to be continued, not started and stopped, because the benefit depends on staying on them.

Pillar 1: sacubitril/valsartan (ARNI) in heart failure

Sacubitril/valsartan combines a neprilysin inhibitor (sacubitril) with an angiotensin receptor blocker (valsartan). Dr. Singh regards it as a drug that has made a huge difference to outcomes, and his position is unambiguous: anyone treating heart failure today should be using sacubitril/valsartan instead of an ACE inhibitor or angiotensin receptor blocker.

The evidence

The PARADIGM-HF trial compared sacubitril/valsartan with enalapril in patients with reduced ejection fraction. It was a multicentre randomised trial with a broad ethnic mix; Dr. Singh highlighted that it included patients from India, Africa and China, so its results apply well beyond European and American populations. Sacubitril/valsartan reduced all-cause mortality, cardiovascular mortality, sudden cardiac death and death from worsening heart failure, and improved quality of life. Later analyses of the trial estimated that it adds roughly one to two years of life expectancy for a typical patient compared with enalapril.

The guideline recommendations are:

• In HFrEF with NYHA (New York Heart Association) class II to III symptoms, an ARNI is recommended.
• In a patient who remains symptomatic on an ACE inhibitor, switch to an ARNI.
• In a patient who cannot tolerate an ACE inhibitor, use an ARNI.

Sacubitril/valsartan dose and safety rules

The usual starting dose is the 50 mg tablet (24/26 mg) twice daily. Dr. Singh starts his patients at half of that, 25 mg by tablet strength (about 12/13 mg), twice daily, and reviews them in his heart failure clinic a week later, where his heart failure nurse checks blood pressure and creatinine before the dose is built up. Patients tolerate the drug well on this schedule.

He gives three firm safety rules:

1. Never combine it with an ACE inhibitor. A patient taking ramipril, perindopril, enalapril or any other ACE inhibitor must stop it for at least 36 hours before the first dose of sacubitril/valsartan. Starting too early increases the risk of angioedema, which is why the 36-hour washout exists.
2. Never use it in a patient with a history of angioedema, whether on an ACE inhibitor or from another cause.
3. Watch renal function closely. Renal impairment is the most important precaution; patients with severe renal or hepatic dysfunction need close monitoring. Dr. Singh treats many patients with kidney problems, under careful surveillance.

The main side effects follow from the drug's potency as a vasodilator: hypotension, hyperkalaemia and, in a small proportion of patients, a cough, because it still acts on the renin-angiotensin system.

Pillar 2: beta blockers in heart failure, low and slow

Beta blockers reduce symptoms, mortality, arrhythmias and hospitalisation, but they must be introduced carefully. Dr. Singh's rule is "low and slow": start with a low dose and build up gradually.

Why patients feel worse first

Patients should be warned that they will feel rough for the first week to ten days, and possibly two weeks. A failing heart compensates with a faster heart rate and depends on its blood pressure to maintain output. A beta blocker slows the heart and, as an antihypertensive, lowers blood pressure, so cardiac output falls at first while the heart adjusts. The dip is temporary. Once the first two weeks are over, the course is upward: better symptoms, better survival, better quality of life, fewer arrhythmias and fewer hospital admissions. In the trials, many patients reported that the first weeks were very bad, and some stopped the drug, which is why counselling at the start matters so much. A heart failure nurse is ideal for this liaison.

Which beta blocker is best in heart failure

Dr. Singh uses bisoprolol, carvedilol or metoprolol succinate, all of which have good outcome data, and does not give atenolol to heart failure patients. He does not use nebivolol, which in his view has not been adequately studied in chronic heart failure; the ESC guideline table does include it, on the basis of the SENIORS trial.

His own default is bisoprolol, because it is given once daily. Since most of his patients also take sacubitril/valsartan, he gives the beta blocker in the afternoon and the ARNI in the morning and at night, spreading the effect on blood pressure across the day. This improves tolerance and adherence.

Pillar 3: spironolactone and other mineralocorticoid receptor antagonists

Spironolactone and eplerenone are both beneficial; a mineralocorticoid receptor antagonist (MRA) blocks the salt- and water-retaining hormone aldosterone. Dr. Singh's dosing advice for spironolactone is specific: 25 mg is sufficient in heart failure. In his account, 50 mg brings no further gain in heart failure outcomes but more renal dysfunction, more hyperkalaemia and more painful gynaecomastia, a frequent reason patients stop the drug. If a patient tolerates 25 mg, he sees no reason to increase it. ESC guidelines list 50 mg once daily as the target dose of spironolactone in HFrEF.

When starting spironolactone, check creatinine and potassium within three days to a week. Eplerenone has more data after a heart attack, in post-infarction heart failure.

Finerenone

For patients with persistent hyperkalaemia or a tendency towards it, or with renal disease, Dr. Singh uses finerenone, a newer and more selective non-steroidal mineralocorticoid receptor antagonist that raises potassium less than spironolactone or eplerenone. It costs more than generic spironolactone. He noted growing evidence that it reduces proteinuria and slows the progression of kidney disease towards dialysis, particularly in diabetes, and advised using it where patients can access and afford it. For context, finerenone's heart failure outcome trial (FINEARTS-HF, 2024) enrolled patients with an ejection fraction of 40% or more, and its kidney outcome trials were in chronic kidney disease with type 2 diabetes; in HFrEF, spironolactone and eplerenone remain the guideline mineralocorticoid receptor antagonists.

Pillar 4: SGLT2 inhibitors in heart failure

SGLT2 inhibitors carry a class I recommendation: every patient with symptomatic chronic heart failure should be on dapagliflozin or empagliflozin, whether or not they have diabetes. They reduce hospitalisation and cardiovascular mortality and are cost-effective. Canagliflozin also has supporting data, mainly from diabetes trials; the heart failure guideline recommendation is for dapagliflozin or empagliflozin. Dapagliflozin and empagliflozin both have strong trial evidence, so the choice can follow availability.

The drugs block sodium-glucose co-transport in the kidney, causing glycosuria. Their cardiac benefit is thought to involve several mechanisms beyond glucose lowering, including antioxidant effects that protect the myocardium.

The DAPA-HF trial

Dr. Singh singled out DAPA-HF, published in 2019, as the trial that changed practice. It was the first randomised controlled trial of an SGLT2 inhibitor in heart failure regardless of diabetes status. Nearly 5,000 patients with established heart failure received dapagliflozin or placebo on top of standard care and were followed for about 18 months.

• The primary outcome, a composite of worsening heart failure and cardiovascular death, occurred in 16.3% of the dapagliflozin group and 21% of the placebo group.
• The number needed to treat was 21: treating 21 patients prevented one primary outcome event.
• The benefit was seen in patients with and without diabetes.

SGLT2 inhibitor side effects: genitourinary infections

Because SGLT2 inhibitors produce glycosuria, they predispose to balanitis in men and genitourinary infections in women. Dr. Singh put the risk of infection at around 5 to 6%. His clinic counsels every patient on two points when the drug is started: personal hygiene is paramount, and any inflammation, balanitis or frequent burning on passing urine should prompt a urine culture. If infection is confirmed, the SGLT2 inhibitor is stopped.

Add-on heart failure drugs when symptoms persist

When a patient on all four pillars is still symptomatic, add-on drugs can improve symptoms and quality of life, though most lack the mortality evidence of the pillars.

• Hydralazine with isosorbide dinitrate. Used for patients who cannot tolerate ACE inhibitors, angiotensin receptor blockers or an ARNI. In NYHA class III and IV patients of African heritage, the combination improves quality of life, and the trial evidence of a mortality benefit comes from self-identified Black patients rather than across all populations. For physicians in Africa, Dr. Singh suggested it can be considered at an earlier stage.
• Vericiguat. A newer drug that stimulates soluble guanylate cyclase and improves cardiac function, but without a proven mortality benefit. Dr. Singh calls it a "super digoxin" and adds it only when everything else has been given and the patient remains symptomatic, provided the NT-proBNP is not very high; it is less beneficial in patients with very high levels.
• Digoxin and ivabradine. Add-ons for symptoms and quality of life.

Dr. Singh's summary of the numbers needed to treat across heart failure therapies showed that every proven treatment saves lives, with some of the lowest figures, in single digits, for resynchronisation therapy in correctly selected patients. Patients still symptomatic on optimal drugs should be referred to a heart failure specialist; the referral article explains when.

Drugs to avoid in heart failure

The drugs to avoid in heart failure are calcium channel blockers (Dr. Singh avoids the whole class), the DPP-4 inhibitor saxagliptin, NSAIDs, class I antiarrhythmics and, in his practice, thiazide diuretics. Dr. Singh was emphatic that withholding drugs without benefit is not enough; drugs that cause harm must also be stopped.

Calcium channel blockers. Dr. Singh's rule is that calcium channel blockers are a "no-no" in heart failure, dihydropyridine and non-dihydropyridine alike, and he avoids verapamil, diltiazem and amlodipine. ESC guidelines classify the non-dihydropyridine drugs, diltiazem and verapamil, as harmful in HFrEF; amlodipine and felodipine are neutral and are the calcium channel blockers that can be used if blood pressure still needs control.

DPP-4 inhibitors. In diabetic patients with heart failure, saxagliptin increases the risk of hospitalisation for heart failure and should be avoided. The diabetes drugs to use are an SGLT2 inhibitor first, followed by metformin.

NSAIDs. Non-steroidal anti-inflammatory drugs retain salt and water, worsen heart failure and worsen renal function. Avoid them.

Class I antiarrhythmics. Flecainide and similar drugs should not be used in heart failure. Dr. Singh reserves amiodarone for a clear indication, such as non-sustained ventricular tachycardia, rather than routine use. In trials such as SCD-HeFT, amiodarone did not improve survival in heart failure; its role is controlling symptomatic arrhythmias.

Thiazide diuretics. Dr. Singh does not use thiazides in patients living with heart failure, preferring a loop diuretic. In hypertensive patients at risk of heart failure, by contrast, thiazide-like diuretics such as chlorthalidone are among the most effective drugs for preventing it. In guideline practice, the loop diuretic remains the diuretic of choice, and a thiazide is reserved for adding to it in congestion that resists a loop diuretic alone.

Supplements. There is no good evidence for routine coenzyme Q10 or multivitamin supplements.

Dr. Biswarup Purkayastha's separate article on newer heart failure drugs, SGLT2 inhibitors and ARNIs offers a second specialist's perspective on the same drug classes. Dr. Singh's answers to doctors' questions on beta blocker tolerance and SGLT2 inhibitor infections are in the Live Discussion, and related material is in the cardiology specialty hub.