My patients have been asking me about the new ‘wonder-drug’ for heart failure, as reported in the ‘Daily Mail’, so I am sure they have been asking you the same thing. The drug is LCZ696* (angiotensin receptor-neprilysin inhibitor) and in the following paragraphs I will try to clarify its role and where it fits in with NICE Guidelines and the historical development of drug treatment for heart failure.
This does come with a few health warnings. The opinions are based on my own interpretations of trials and so shouldn’t be taken as formal guidelines. New drugs are exciting, but many more patients thank me for referring them to the Community Heart Failure Service than thank me for starting a new drug. Teamwork between Cardiologists, General Practitioners, Heart Failure Nurses, Carers, Patients, District Nurses and Pharmacists is most important and best co-ordinated by a Heart Failure Service.
HFPEF and HFLEF
These are the new abbreviations in the NICE Guideline from last year. HFLEF is the ‘common heart failure’ with low ejection fraction that is studied in most of the drug trials. Heart failure with preserved ejection fraction (HFPEF) has many other names including diastolic heart failure, HeFNEF (heart failure with normal ejection fraction) and some uncharitably call it being old and fat. Trials on HFPEF are generally negative and treatment includes diuretics, rate control if in atrial fibrillation (AF), blood pressure control, diet and exercise.
William Withering described the use of Digoxin for ‘dropsy’ in 1785. It is possible that many of his successfully treated patients had rheumatic mitral valve disease and AF, but modern trials in patients with sinus rhythm have shown improved symptoms and reduced hospitalisation.
Angiotensin converting enzyme inhibitors (ACEI) and Angiotensin receptor blockers (ARB)
Derived from Brazilian Pit Viper venom, these are the most useful and best-studied agents for HFLEF. Ramipril, Lisinopril and Enalapril all have excellent evidence and are probably equivalent. Perindopril and Captopril have less robust evidence. ARBs should be used when there is ACEI allergy or severe intolerance, but are not equivalent in terms of efficacy.
Developed by Sir James Black in 1958, these agents are now recommended for most HFLEF patients. NICE and the Cochrane Systematic Review emphasise that Bisoprolol and especially the more cardioselective Nebivolol should be used by patients with lung disease such as COPD, but not patients with true moderate or severe asthma. Carvedilol is probably the best beta-blocker, but does cause bronchospasm in susceptible patients.
Spironolactone and Eplerenone are recommended for patients who remain moderately symptomatic, despite conventional treatment. Eplerenone has a licence for post-myocardial infarction heart failure, but is more expensive than Spironolactone and there is no evidence that it is more effective.
Funny channel inhibitor (Ivabradine)
I don’t know why these channels in the sinoatrial node are funny, but when inhibited, the heart rate decreases without reduction in blood pressure or cardiac contraction. The BEAUTIFUL Study in patients with heart rate >60/min was negative. The drug company was very brave and ran a follow-on study in patients with heart rate >70/min for two reasons. Firstly, these large trials are very costly and secondly, they called it the SHIFT Study that lends itself to mispronunciation, à la James Naughtie, if results are not favourable. Results were positive with respect to symptoms and reduced hospitalisation, but only in those with heart rate >70/min and in sinus rhythm. This study was too late for NICE Guidelines and in future will probably be given similar support to digoxin, which will be considerably cheaper.
Angiotensin receptor-neprilysin inhibitor (LCZ696)
Published in September 2014, the PARADYM-HF study compared LCZ696 with probably the best current disease-modifying drug, Enalapril. LCZ696 is a combination of Valsartan and a neprilysin inhibitor. Neprilysin is an enzyme that inactivates natriuretic peptides, bradykinin and adrenomedullin. The trial was stopped early because LCZ696 clearly outperformed Enalapril in all endpoints including all cause mortality, but is only useful when EF <40%. It is probably too late to buy shares in Novartis, but if you have some already, well done!
Dr Ian Beeton
Ashford & St Peter’s Hospitals NHS Foundation Trust
*LCZ696 is not currently commercially available.