Background

Paris, France | The Grand Debate 1: Neprilysin inhibitor - Vasodilators: LCZ 696 (Sacubitril/Valsartan)

A new type of session in the programme of the ESC Heart Failure congress consisted of Grand Debates on the most popular controversies in the management of heart failure, in which specialists defended a position in front of their opponent. The first debate dealt with the question whether the new angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan is ready for prime time as a first-line therapy.

Professor Eugene BRAUNWALD (Boston, USA) gave an introduction to the topic by showing how much treatment of HF has advanced since he graduated in 1952. The first major breakthrough in treatment options was a publication on the use of benzothiazide dioxide in 1957. Later, many other agents have been added to the therapeutic options to help HF patients, as well as devices. The latest addition is the ARNI sacubitril/valsartan. Professor Braunwald noted that all previous agents have been thoroughly accepted and implemented in daily practice. The question now is whether sacubitril/valsartan will continue this trend.

Prof. John MCMURRAY (Glasgow, United Kingdom) defended the proposition that yes, sacubitril/valsartan is ready for prime time as a first-line therapy. He focussed on quality ánd quantity of life, on what physicians can offer their patients by giving them the ARNI. In PARADIGM-HF, adding sacubitril/valsartan to conventional therapy (RAAS blockade and beta-blocker) yielded a 20% reduction in the primary composite outcome of CV death and HF hospitalisation and 16% reduction in all-cause mortality, in HF patients in NYHA class II-IV with LVEF≤40%. Based on these results, McMurray argued that there is little reason not to give it to patients. Still, the results of PARADIGM-HF have been criticised. He wondered out loud what the cost in suffering and of lives is by entertaining these arguments.

He thus examined the validity of the criticisms. The selected patients have been topic of debate; they would be too young, too few hospitalised patients, not enough NYHA class IV patients, and no BNP/NTproBNP level was required for enrolment. Yet, when he compared baseline characteristics of PARADIGM-HF with the ESC long-term registry of ambulatory patients with LVEF <40%, the most relevant characteristics are remarkably similar. Thus, the PARADIGM-HF population does not seem to be as selected as said. Moreover, a study assessing the effect of sacubitril/valsartan according to age in PARADIGM-HF found a consistent benefit across the age spectrum. Similarly, the effect of treatment on the primary endpoint has been shown to be consistent across quartiles of NT-proBNP level.

Another criticism has been the prerequisite of prior ACE inhibition (ACEi). McMurray noted that indeed you could start a ACEi-naïve patient on half-dose ACEi for a month before switching to sacubitril/valsartan, but a caveat is that physicians commonly think ‘my patient is stable on current therapy, why should I change anything? I’ll wait and see how he/she gets on.’ However, he pointed out that 33% of the first primary endpoints were CV deaths, and 61% of these were sudden.

The run-in phase has also received much attention and criticism. It was necessary to ensure that sacubitril/valsartan would be compared an evidence-based dose of enalapril. This actually reflects clinical practice. Even if the analyses would account for those who dropped out if they were included in the analysis, this would not affect the results, McMurray said.

The level of recommendation has also been debated, since it is based on a single trial. A very large trial though, with a very small P-value. On a statistical level, the value of these data equals 4 or 5 smaller trials.

Finally, there have been safety concerns, labelled scaremongering by McMurray. For instance, the theoretical risk of cognitive problems. Neprilysin is, however, one of over 20 amyloid beta-peptide clearance mechanisms in the brain, including ACE. There has been no consistent evidence from experimental or genetic studies that neprilysin is involved in the development of dementia.

He concluded that these arguments may be the reason why both FDA and EMA approved sacubitril/valsartan to reduce the risk of CV death and hospitalisation in patients with chronic HF and reduced ejection fraction.

Dr. Mariell JESSUP (Boston, United States of America) then defended the contra position, by focussing on the words ‘first line therapy’. That implies starting a drug when HF is first identified. Generally, that means starting beta-blocker and/or ACEi. Are we now saying that we will start with giving the ARNI, she wondered? In patients who have not used beta-blockers or ACEi yet?

Although she very much appreciates the trial results, there are a few things she liked to say. To start with, the Guidelines do not recommend the use of ARNI as first line therapy: they recommend using ARNI in patients who are still symptomatic despite using ACEi, ARBs and beta-blocker.

Also, she noted that PARADIGM-HF studied an enriched patient population, not necessarily applicable to the world of HF or even HFrEF. Enrichment strategies in trials include decreasing heterogeneity for instance by adding a run-in phase, prognostic enrichment through enrolling patients who were recently hospitalised, or by requiring a minimum BNP level, or predictive enrichment using companion diagnostics. A run-in period /per se/ is not a bad thing, Jessup noted, but you need to understand how it translates to the clinic.

Studies have shown that mortality is highest in the first year after hospitalisation for HF, with higher mortality rates for acutely compensated chronic HF as compared to /de novo/ HF. Thus, these are different clinical entities.

A lot happens when persons first find out that they have HF. Therapy will be initiated and various medications will be added. Jessup acknowledged that at some point it will probably be the right thing to add ARNI at the beginning of therapy, but that is not what PARADIGM-HF told us about. We should be careful in extrapolating, as we cannot predict what will happen when we expand the population.

As a final caveat she did mention that the cost of the drug is a problem. It has been shown, and anecdotally confirmed for other countries, that 30% of American prescriptions are not picked up by patients when they find out about the price.

She concluded by saying that sacubitril/valsartan represents a great new drug, a great addition to the physician’s armamentarium. But we should learn how it can best be used. For the moment we should use it as was done in the trial, and not expand too much.

McMurray responded by emphasising that he really feels that patients should receive the best drug available, to benefit from the lower mortality, HF hospitalisations and health-related quality of life. Jessup agreed but also appreciates that there are still barriers in the way of its use. She advocates that we find out what the barriers are and try to overcome them. She concluded “we should not stay in what is at best an intellectual debate, but should move on together to find out how we can get the best care to our patients.”

Braunwald noted at the end of the session that patients on enalapril have been shown to experience a clinically important deterioration of quality of life, over a period of 8 months. McMurray explained that indeed, patients are not doing as well as we like to think. That is why he would like to switch to ARNI in many patients. He accepts that using sacubitril/valsartan as first-line therapy would mean an extrapolation of the data. To him, it makes no sense to start ACEi and do all necessary tests to ensure the patients doesn’t have hypotension, hyperkalaemia, aberrant electrolytes, etc, to then switch after 30 days and do it all over again.

Braunwald closed the session by noting that this was not so much a debate, but rather a good conversation. Nevertheless, when asked to vote who convinced them most, the audience gave 60% of votes to Jessup and 40% to McMurray. Whether this reflects how much the audience appreciated the good dose of humour they both inserted in the debate, or the clinical standpoint, is unclear.

Disclosures

Our coverage of ESC HF 2017 is based on the information provided during the congress.