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New heart failure drug 'could replace ACE inhibitors and ARBs'

A new drug therapy for heart failure could end up replacing ACE inhibitors and angiotensin receptor blockers (ARBs) as the mainstay of treatment, said researchers who unveiled findings of a pivotal trial that GPs say could ‘transform’ the management of heart failure.

The agent - a combination of the neprilysin inhibitor sacubitril and the ARB valsartan - led to marked improvements in survival and hospitalisation rates compared with ‘gold standard’ treatment with enalapril.

GP experts said the new agent - which is not yet approved - had shown such a big improvement on current standard treatment it could well be a ‘game changer’ in the management of heart failure.

They added it was unclear how soon it could be adopted in the UK and that further long-term evaluation of the drug is still needed.

The trial randomised 8,399 patients with class II to IV heart failure and a left-ventricular ejection fraction of less than 40% to take the angiotensin receptor-neprilysin inhibitor - dubbed LCZ696 - at a dose of 200 mg twice daily, or enalapril 10 mg twice daily, on top of other recommended therapies.

Novartis, which is developing LCZ696, announced earlier this year that the trial had been stopped early because of a clear benefit with the new treatment, but details of the findings were sketchy.

The full results, announced at the European Society of Cardiology annual congress and published in the New England Journal of Medicine over the weekend, showed that over the median follow-up period of 27 months the primary endpoint of death from cardiovascular causes or hospitalisation for heart failure occured in 22% of patients in the LCZ696 group compared with 27% of the enalapril patients.

In relative terms, this meant LCZ696 reduced the risk of cardiac death or heart failure hospitalisation by 20% - as big a reduction as enalapril achieved compared with placebo, according to the researchers.

Secondary outcomes including all-cause mortality and symptoms and physical limitations of heart failure were also reduced significantly by the new drug.

On the downside, LCZ696 did cause an increase in hypotension, although the study investigators said this was rarely serious enough for a patient to discontinue the medication.

The drug is now on a ‘fast-track’ for approval by the US drugs regulator and is likely to be put through European approval soon.

Professor Milton Packer, co-lead investigator of the study and a cardiologist at the University of Texas Southwestern Medical Centre, said physicians would be compelled to use the drug once it becomes available.

Professor Packer said: ‘Given the survival advantage of LCZ696 over currently available drugs, once this drug becomes available, it would be difficult to understand why physicians would continue to use traditional ACE inhibitors or ARBs for the treatment of heart failure.’

Dr Terry McCormack, secretary of the British Hypertension Society and a GPSI in cardiology in Whitby, North Yorkshire, told Pulse the findings did seem strong enough to suggest they would transform heart failure management in the future, although it could take some time to adopt the new treatment even if it is approved in the UK, because standard ACE inhibitor and ARB treatments are available as cheap generics.

Dr McCormack said: ‘It is a game changer. And it will cause headaches for medicines management because we’ve got the off-patent drugs already.’

He added: ‘The downside of it is it lowers your blood pressure and that’s not necessarily a good thing if you’ve got heart failure. So that’s the challenge - but the good side is has a very obvious long-term mortality data. The regulators say they want outcomes evidence - and here it is.

Dr Ivan Bennet, GPSI in cardiology and chair of Manchester CCG, said LCZ696 would be a ‘welcome new option’ and that the size of the effect on outcomes suggested it could be cost-effective - but cautioned it may not help all groups of patients and that further analyses were needed.

He said: ‘This study certainly looks like it is showing significant benefit for this new combination of drugs LCZ696. However, as usual, before going over board with excitement there are a few caveats to introducing this to our patients.’

Dr Bennet noted that black, Asian and native American groups did not gain the same benefits from the drug - although these groups were relatively under-represented in the trial - and that the study did not address how heart rate could have influenced the outcome, while more data are needed on the safety of the new treatment.

He added: ‘We don’t know the cost benefits either, but if they reduce hospitalisation by as much as 20%, it is likely to be cost-effective.

‘All in all, LCZ696 is to be welcomed as a new option, but it won’t necessarily help everyone, and it does not mean that we can ignore current recommendations about medicine optimisation, heart rate control, and patient education.’

NEJM 2014; available online 30 August

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