New Heart Failure Drugs: SGLT2 Inhibitors, ARNIs and More

The new heart failure drugs are SGLT2 inhibitors such as empagliflozin and dapagliflozin, the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, mineralocorticoid receptor antagonists including the non-steroidal finerenone, and the soluble guanylate cyclase stimulator vericiguat. They are used alongside evidence-based beta blockers such as bisoprolol, carvedilol and metoprolol succinate, which remain one of the foundational therapies for heart failure with reduced ejection fraction.

Medical treatment of heart failure has changed completely in the last few years. For Dr. Biswarup Purkayastha, Consultant – Heart & Lung Transplant and Vascular Surgery, Artemis Hospitals, Gurugram, India, the practical consequence is blunt: in his view, keeping a patient on digoxin or an older, non-specific beta blocker does little for them, and time spent on such regimens is time lost before referral. His criticism is aimed at older, non-specific agents, not at evidence-based beta blockers. His approach rests on four newer drug classes, conservative titration, a precisely measured ejection fraction, and specific adjustments when heart failure coexists with HIV and tuberculosis. The broader context of why heart failure presents earlier and later in Africa is set out in the complete guide to heart failure and coronary artery disease in Africa.

The new heart failure drugs and how they are used

Four newer drug classes now anchor heart failure treatment: SGLT2 inhibitors, ARNIs, mineralocorticoid receptor antagonists and soluble guanylate cyclase stimulators. Dr. Purkayastha's choices and dosing within each class follow.

SGLT2 inhibitors: empagliflozin vs dapagliflozin

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, the "flozins", make the kidneys pass more glucose and salt into the urine, and they are now a core heart failure therapy. Dapagliflozin was the first molecule in the class to reach heart failure practice, and empagliflozin followed.

Where a clinician has no specific reason to choose one over the other, Dr. Purkayastha's rule of thumb is simple: choose empagliflozin. His reasoning is renal. Empagliflozin, he notes, does not require dose adjustment even when the glomerular filtration rate falls below 30 ml per minute. In heart failure, both empagliflozin and dapagliflozin are given at a fixed dose of 10 mg once daily; empagliflozin can be started at an eGFR down to 20 ml/min/1.73 m², and dapagliflozin down to 25. That matters for the patients who most need long-term SGLT2 therapy and are most likely to have impaired kidneys:

• patients with chronic kidney disease
• patients with a vasculitis or vasculopathy affecting the kidney
• diabetic patients predisposed to diabetic kidney disease

In his unit's practice, empagliflozin is used considerably more often than dapagliflozin for these groups.

Sacubitril/valsartan (ARNI): the new first line

Angiotensin receptor-neprilysin inhibitors (ARNIs) combine sacubitril with valsartan. They work by blocking neprilysin and so enhancing the natriuretic effect of the natriuretic peptides, and they prevent the harmful remodelling that drives progressive heart failure. In Dr. Purkayastha's account they have largely replaced ACE inhibitors as the first-line drug for heart failure.

Who should receive it. He is most interested in starting sacubitril/valsartan in a patient with an ejection fraction below 45%, and especially below 35% with a high NT-proBNP level, a blood marker that rises when the heart is under strain.

How it is dosed. The drug is started low and built up gradually:

• Begin low. The labelled starting strength is 24/26 mg twice daily; in the patient population he treats he frequently starts lower still, at 25 mg once a day.
• Build up in steps, weekly in his practice and every two to four weeks on the label, towards the target of 97/103 mg twice daily, as blood pressure, kidney function and potassium allow.

The low starting dose reflects a broader principle in his practice: the drug should be started at the lowest possible dose and increased only as the patient tolerates it. Clinicians' questions on sacubitril/valsartan, drug interactions in HIV and tuberculosis, and refractory oedema are answered in the Live Discussion from the masterclass.

Mineralocorticoid receptor antagonists: from spironolactone to finerenone

Mineralocorticoid receptor antagonists such as spironolactone have long been part of heart failure treatment. A newer group, the non-steroidal MRAs, is represented by finerenone, which he includes among the agents now available to clinicians.

Soluble guanylate cyclase stimulators

This class raises cyclic GMP levels and improves vascular function. Riociguat was first used for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Vericiguat is the newer agent in the class and is used in heart failure with reduced ejection fraction. Dr. Purkayastha regards patients with heart failure and an ejection fraction below 45% as candidates for vericiguat; its licensed use is in symptomatic heart failure with an ejection fraction below 45% after a recent worsening event, such as a hospital admission or the need for intravenous diuretics.

Investigational agents

Beyond the approved classes, he points to cardiac myosin activators such as omecamtiv mecarbil, studied in the GALACTIC-HF programme. He describes these as still investigational: in research and trials, and yet to reach routine clinical use.

A note on brands and availability

In presenting these drugs, Dr. Purkayastha deliberately showed international, European-manufactured brands that are widely available across large parts of Africa, so that clinicians could recognise what they can actually prescribe. He stated that he has no consulting relationship with any of the manufacturers, in an independent or an official capacity.

At what ejection fraction do heart failure drugs work?

Ejection fraction is the percentage of the blood in the left ventricle that the heart pumps out with each beat. Guideline-directed medicines benefit patients across the reduced range, and several also help up to about 50%. Below 25%, in his view, the heart also needs specific attention, and devices and transplantation enter the discussion, as covered in heart failure surgery: valve repair, LVADs and transplant.

Why the number has to be exact

Because treatment decisions turn on these thresholds, he is wary of loosely reported ejection fractions such as "30 to 35%" or "20 to 30%". In his words, a 20% ejection fraction is a completely different situation from 30%. His instruction is to have the ejection fraction measured by Simpson's method, or another defined method, and to work from a single fixed number.

Treating heart failure in patients with HIV and tuberculosis

The overlap of heart failure with HIV and tuberculosis is common across the region, and it changes both drug selection and dosing.

Tuberculosis: a prothrombotic state

Tuberculosis is associated with an increased risk of venous thrombosis, particularly in the first months of treatment. Routine antiplatelet or anticoagulant prophylaxis is not recommended; the decision rests on each patient's thrombotic and bleeding risk. Rifampicin, a core tuberculosis drug, strongly reduces the effect of warfarin, so any anticoagulation during tuberculosis treatment needs close INR monitoring.

HIV: interactions through CYP3A4

Many antiretroviral drugs are metabolised through CYP3A4, a liver enzyme that breaks down many medicines, and some inhibit or induce drug-metabolising enzymes, so they interact with a range of cardiac medicines. The ones he highlights are:

• warfarin
• beta blockers

His approach is to consult the antiretroviral therapy clinic or the infectious disease specialist about the specific interactions of the regimen the patient is on, and to alter the cardiac doses accordingly. As a working rule, more often than not the warfarin dose has to go up and the beta blocker dose has to come down.

Refractory oedema: when swelling will not resolve with diuretics

Oedema is swelling caused by fluid collecting in the tissues. A frequent and frustrating scenario is the patient with HIV, pulmonary tuberculosis and low blood pressure whose feet remain swollen despite treatment. Dr. Purkayastha's first step is diagnostic rather than therapeutic: obtain a recent echocardiogram and establish heart function precisely.

Below 20%, oedema becomes hard to clear. If the ejection fraction has fallen below 20%, peripheral oedema is much harder to control. Diuretic resistance is common, and escalating the dose alone often fails; sequential nephron blockade with a thiazide or acetazolamide is the usual next step.

Mechanical fluid removal. In a failing heart with substantial fluid accumulation, where diuretic therapy has failed, one option is ultrafiltration, filtering excess fluid out of the blood through a machine, with a device such as the Aquadex SmartFlow System. He describes it as a miniaturised device that removes excess fluid at a controlled hourly rate. For an intractable patient whose oedema persists whatever the diuretic dose, he regards it as a logical next step.

Why peritoneal dialysis is a poor fit here. In a hypertensive patient there are more options, including diuretics and ambulatory peritoneal dialysis. In a patient with a communicable disease, however, a device in a body cavity that is open to the outside world raises the risk of infection and spread, and he does not consider it a feasible or acceptable solution.

Recognising the endgame. With an ejection fraction below 25%, and particularly below 20%, Dr. Purkayastha is candid that this is the endgame: there is not much more that can be offered to the heart itself.

Heart failure drug strategy: four principles

Read as a whole, Dr. Purkayastha's medical approach rests on four principles:

1. Retire archaic regimens. In his view, digoxin and older non-specific beta blockers should give way to SGLT2 inhibitors, ARNIs, MRAs and, where indicated, vericiguat, alongside evidence-based beta blockers.
2. Dose for the patient in front of you. Start ARNIs at the lowest dose and titrate every two to four weeks; prefer empagliflozin when kidney function is impaired.
3. Measure precisely. A single ejection fraction figure, measured by a defined method, decides whether medicine alone is enough.
4. Adjust for infection. In tuberculosis, anticipate thrombosis; in HIV, consult the antiretroviral team and expect to raise warfarin and lower beta blocker doses.

When the ejection fraction falls below the range in which drugs work, the next decisions belong to the full heart team, and early referral to a centre that can offer devices or transplantation becomes the most important intervention of all.