Critical care
A diagram showcasing left ventricular hypertrophy, an event that increases the chances of fatality from heart failure.
HFrEF. Mineralocorticoid receptor antagonists (MRAs) are the go-to drug for treating advanced heart failure. In the past few years, however, two drugs have demonstrated particular potential in the treatment of HFrEF, Bitar explains. Marketed under the brand name Entresto, angiotensin receptor neprilysin inhibitors (ARNi) have been shown in trials to be more effective at prolonging life than ACE inhibitors, and Bitar believes their use will become much more commonplace. Entresto combines two drugs traditionally used to reduce blood pressure: sacubitril and valsartan. Sacubitril works by blocking the breakdown of natriuretic peptides produced in the body, while valsartan blocks the action of angiotensin II – the hormone that causes left ventricular hypertrophy and increases mortality risk in heart failure patients. The second promising type of drugs are sodium glucose cotransporter 2 (SGLT2) inhibitors, which have traditionally been used to treat diabetes. Two major trials, DAPA-HF (assessing dapagliflozin) in 2019 and EMPEROR-Reduced (assessing empagliflozin) in 2020 showed that SGLT2 inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with HFrEF.
Treatment for HFpEF is on the horizon HFpEF has proved harder to treat than HFrEF. “Management focuses mainly on making sure that patients don’t build up any fluid by using diuretics, and controlling their blood pressure,” says Bitar. But this could change. Stefan Anker, professor of cardiology at Charité University in Berlin, was involved in another trial, the EMPEROR-Preserved trial, which looked at using empagliflozin to treat HFpEF patients. The results, published in August 2020, “showed for the first time a successful therapy for HFpEF patients”, says Anker. The ongoing DELIVER trial is currently looking at the use of dapagliflozin to treat HFpEF patients.
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Anker highlights two vital changes to the European Society of Cardiology guidelines on treating heart failure, published in 2021. The guidelines recommend using four classes of medicine for early treatment of HFrEF: ARN inhibitors, beta-blockers, MRAs and SGLT2 inhibitors. In the past, the advice has been to prescribe patients a maximum dose of one type of heart failure drug, and then move on to the next. “The guidelines now emphasise an approach where you give the patients, as quickly as possible, at least four classes of drugs that are all shown to be survival- prolonging,” says Anker. Within four to eight weeks, the patient should be taking all four drugs, but not necessarily at the maximum dose. This is a highly significant change that buys the patient time, he says: “You can only benefit from a drug that you take. If you don’t take the drug, it can’t exert benefit, so shortening that period of time is really a big step forward.” The second new recommendation requires physicians to personalise the therapy, by factoring in differences in aetiology and comorbidities. Anker says: “When you want to consider therapy beyond the four foundational therapies, you should take the phenotype of the patient into account and then individualise therapy for the valve problems, for the sleep apnoea, for the iron deficiency, for the high heart rate.” Looking further ahead, says Bitar, two drugs have undergone successful phase III trials. The first is omecamtiv mecarbil, which “makes the heart muscle squeeze a bit more efficiently without increasing how much energy the heart needs”. The 2020 study reduced the amount of time until patients either died from heart-related causes or needed treatment for heart failure by 8%. The second drug is the soluble guanylate cyclase stimulator, which a 2020 trial concluded led to both lower risk of death and lower risk of being admitted to hospital. “Those would be the two most promising candidates for the near future,” he says.
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