ESC debate | First-line therapies in HFrEF - ACE inhibitors or sacubitril/valsartan?
Chairpersons: Gerasimos Filippatos (Athens, Greece) and Mariell Jessup (Hingham, MA, USA)
Before anything was said about the topic, the audience voted on the statement “Sacubitril/valsartan should be the starting treatment in heart failure with reduced ejection fraction (HFrEF) patients”. With exactly 50-50, this was a perfect starting point of what would turn out to be a lively debate, in which both speakers did their best to convince the audience to move to their standpoint. But first, dr. Filippatos gave an introduction to the debate.
Positioning of the topic
Gerasimos Filippatos (Athens, Greece)
Dr. Filippatos re-iterated what professor Eugene Braunwald had presented during a debate at Heart Failure 2017 in Paris: heart failure therapy according to the standards in 1952 consisted of strict bed rest, sedation and oxygen. In addition, a diet with reduced calories and 200-400 mg/day sodium and vitamins was given. Digitalis was almost universal, organic mercurial and NH4Cl were given as diuretics and additionally, venesection, rotating tourniquets and Southey tubes (inserted into edematous peripheries, allowing some drainage of fluid) were considered.
Things have changed since then. We now have evidence-based therapy that came forth from the observation that HF is accompanied by adverse neurohormonal activation. Plasma norepinephrine levels and plasma renin activity are typically increased in HF patients. Over the years, several therapeutic agents have been developed, and therapy with ACE-inhibition (ACEi), addition of beta-blockers and later also mineralocorticoid receptor antagonists (MRAs) have shown incremental mortality benefits. Another evidence-based strategy that lowers all-cause mortality is cardiac resynchronization. Thus, multiple randomized clinical trials (RCTs) conducted over the past decades have provided us with several evidence-based treatments for HFrEF, which have been included in international guidelines.
Several important, large trials have been conducted after publication of the 2012 ESC Guidelines on management of HF. Filippatos considered BB-meta-HF worth mentioning: a large meta-analysis that evaluated the efficacy of beta-blockers in preventing death. This analysis demonstrated that beta-blockers are not as good in HF patients who also have atrial fibrillation (AF), as compared to in HF patients in sinus rhythm. This is relevant, as many HF patients already have AF or may develop it at some point. This observation is mentioned in the ESC HF guidelines, but not included in the recommendations.
The next important trial is clearly the PARADIGM-HF trial, in which the efficacy of angiotensin-neprilysin inhibition with sacubitril/valsartan was compared with enalapril. The positive results are well known, and they have already been implemented in recent HF guidelines. Small differences in treatment approach exist between the European and American guidelines. The 2016 ESC guidelines recommend starting HF treatment with ACEi plus beta-blocker, then add MRA and if the patient is still symptomatic, replace ACEi with the angiotensin-neprilysin receptor inhibitor (ARNi) sacubitril/valsartan. The American ACC/AHA/HFSA guidelines advise to start with ACEi plus beta-blocker, and consequently, depending on patient characteristics, move to MRA or ARNi, among several other options.
Now, what do the debaters think of this; should the guidelines be updated to including sacubitril/valsartan as first-line treatment, or are they good as they are for the time being?
Sacubitril/Valsartan should be the starting treatment in HFrEF patients – PRO
Professor Milton Packer (Dallas, TX, USA)
Prof. Packer commemorated that exactly four years ago, he presented the results of the PARADIGM-HF trial at the ESC congress in Barcelona. He expressed his surprise that we are still debating the implications of this trial, even though the design was so well done and the results were so positive.
The study included patients already on long-term treatment with inhibitors of the renin-angiotensin system (RASi), although often at sub-target doses. The PARADIGM-HF study included a run-in phase to test tolerance to target doses of the study drugs, before patients were randomized to either enalapril or sacubitril/valsartan (both about 4200 patients). The results of the PARADIGM-HF trial were persuasive, with a reduction of 20% (95%CI: 0.71-0.89, P=0.00008) in CV death, which reflected a median prolongation of life of 1.5-2 years. When comparing this effect to that achieved with conventional inhibitors of the RAAS system, a doubling of the benefit on CV death is seen.
Thus, acknowledging this benefit, Packer stated that the question on the use of sacubitril/valsartan in chronic HF instead of conventional RASi, is not IF to use it, but WHEN.
To try to answer this question, he showed a graph of time to first hospitalization for HF during the first 30 days following randomization in the PARADIGM-HF trial. The curves of the cumulative event rates diverge within ten days and this difference becomes statistically significant within 30 days (HR: 0.60, 95%CI: 0.38-0.94, P=0.027), showing a lower event rate for sacubitril/valsartan. Thus, a very rapid effect of ARNi therapy is seen. Packer therefore thinks that physicians cannot delay the replacement of ACEi with sacubitril/valsartan in stable patients with mild-to-moderate symptoms. Sacubitril/valsartan not only reduced CV death, but also the risk of resuscitated and non-resuscitated sudden cardiac death by 22%, and the risk of sudden cardiac death in patients with an ICD by 51%. So, in answer to his own question of not if, but when, he exclamated 'NOW!' Of course, that raises the next question of ‘when exactly?’.
Should the switch to sacubitril/valsartan occur before other interventions? For instance, before uptitration to target doses of an ACEi or ARB? Reaching target doses of RASi is not associated with a mortality benefit (as shown in the ATLAS and HEAAL trials), while adding neprilysin inhibition to RASi, by reaching target doses of sacubitril/valsartan does yield a mortality benefit. Moreover, in the PARADIGM-HF trial, treatment with sacubitril/valsartan showed less renal insufficiency than enalapril treatment. And, even if sacubitril/valsartan was not taken at target dose, superiority of treatment persisted. Thus, Packers answer is 'YES!' Switch to sacubitril/valsartan should occur before uptitration to target doses of ACEi or ARB.
What about whether the switch should occur before initiation of treatment with an MRA? Packer showed a graph demonstrating that sacubitril/valsartan prevents severe hyperkalemia in patients taking MRAs, when compared with enalapril. Thus, he concluded that indeed the switch should be made before starting an MRA.
Then, does that mean that sacubitril/valsartan should be the starting treatment for HF? He noted that if a patient is currently not taking RASi, they should first be evaluated on a low dose of a RASi for a short time, before being switched to sacubitril/valsartan. Is this a violation of the statement on starting treatment? He thinks not. Because, he argued, how often does one actually start RASi in a HF patient? Hypertension, diabetes, high-risk coronary artery disease and/or left ventricular dysfunction often precede chronic HF. In all of these conditions patients often already receive a RAS blocker. So, all you have to do in these patients is switch to sacubitril/valsartan, which means it is the starting treatment for HF when this diagnosis is made. 'Just like in PARADIGM-HF,' Packer added.
Sacubitril - Valsartan should be the starting treatment in HFrEF patients – CON
Professor Adriaan Voors (Groningen, Netherlands)
Prof. Voors set out to defend the CON-position. Yes, he thinks sacubitril/valsartan is a good drug, but he is convinced that does not mean it should be used as starting treatment just yet. To convince the audience of this viewpoint, he started by showing the last slide of Packer’s presentation of the PARADIGM-HF results in 2014. The results for sacubitril/valsartan compared with enalapril were very convincing, both with regard to efficacy and tolerability. That led to sacubitril/valsartan already making it into the 2016 ESC HF Guidelines. In the Guideline writing committee, there was complete agreement on that it should be included, but the exact position of sacubitril/valsartan was topic of debate. The guidelines state that ‘sacubitril/valsartan is recommended as a replacement for an ACEi to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACEi, a beta-blocker and an MRA’. It has a class I level B recommendation, which means that those patients should receive it.
That indeed raises the question of why make things complicated and first uptitrate? To Voors it is clear: because this was the study design of PARADIGM-HF. It was a good design, which led to good results. Patients could only enter the study if they received at least half of the recommended doses, for at least four weeks before the screening visit. Voors was involved in the BIOSTAT-CHF study, which was specifically designed to study up-titration of ACEi/ARBs and/or beta-blockers in 2100 HFrEF patients from 69 centers across Europe. After an up-titration phase of 9 months, 22% reached the recommended dose of ACEi/ARB and 53% reached at least 50% of the recommended dose. These results show that based on these treatments, a first selection of patients eligible to enroll in PARADIGM-HF took place. Then a run-in phase for enalapril followed in the trial, and after that a sacubitril/valsartan run-in phase. This means that the positive results were obtained in a selected group of patients. That raises the question whether the PARADIGM-HF findings can be extrapolated to other patients, for instance de novo patients and treatment naïve patients. Voors thinks they cannot.
He turned to studies that compared those with new onset HF with those with existing HF, to prove his point. Differences are seen between these groups of patients, quite a few significant ones actually. We have learned in the past that if the population is slightly changed, we cannot assume that we will see the same benefit. More importantly, we can do harm. Another reason to be conservative (in guidelines) is that concerns have been raised about amyloid deposition in the brain. In the tested populations this does not seem to be a danger. If there is a risk, it might be acceptable in patients severely affected, but not in extrapolated patients. Financial arguments are also relevant: we should be careful with resources and not give new drugs to those for whom an effect has not been proven yet.
To finish, Voors noted that current guidelines agree with him; the Americans say first start with ACEi, and then switch to sacubitril/valsartan. The Canadian guidelines say the same thing, and Australia just published a new version, which also states the same.
Packer, in his rebuttal, was not convinced. He said the question today was about HFrEF: this is not a totally different population. Secondly, about entry criteria; Voors had said that one should tick all entry criteria before considering sacubitril/valsartan. But, everybody uses ACEi for their patients, but how many physicians remember the entry criteria of the ACEi trials?
By drawing a parallel to cancer, he made the point that if a disease is severe enough; one would like to take the newer agent with the double effect rather than conventional treatment. In this situation, we should not be worried about accumulation of amyloid. A doctor will not say: 'I should first give you less efficient drug', because the patient does not care what is in the guidelines; the patients just wants to feel better.
In his rebuttal, Voors continued on this patient’s scenario. What if the patient had a brain tumor, but the treatment is for pancreas cancer? If you give the treatment, would that make you a good physician? Yes, we should give the best treatment that we have, but we should also stick to the evidence. 'Let’s start with those patients that fulfill the criteria,' Voors proposed.
He also wondered how to go about patients who are well on treatment, should they be switched? He thinks that if we get more experienced with the drug, the criteria can be loosened up a little bit. But that is a different situation than extrapolating to for example de novo patients. Some of these may even recover. We need to know underlying diseases; patients are not all the same.
Thus, Voors concluded that we have to be patient, we have to do things in the right order: first uptitrate, then switch. Then we are the best doctors.
Many questions from the audience came in, for instance what to do with treatment when the ejection fraction normalizes. Voors answered that he does not stop treatment, because one does not know whether it improves because of treatment. In chronic HF it is highly likely that it is because of the drug; thus it makes sense to keep it. In de novo patients normalization of ejection fraction might be the normal course of disease.
A question for dr. Packer was whether there is still a role for ACEi in HF. Of course, he answered, as ‘there will be people who do not tolerate sacubitril/valsartan. Some people develop symptomatic hypotension that does not respond to dose adjustment. These people will be on conventional RAS blockers.’
Several questions were asked about the dose and treatment decisions in specific patients. Voors shared that it typically takes 3-6 months to uptitrate treatment. Packer agreed but said that it should not take so long. “Look at the event curves: patients are dying during uptitration!’
Voors replied that it is risky if patients get too much beta-blocker. He advocates ’Start low, go slow.’ Packer created consensus by suggesting to uptitrate, but to go quicker. Do not wait 6-8 weeks before going to the next step. Depending on tolerability, we can uptitrate every 2 weeks or so.
Jessup expressed her hope in her concluding remarks that the audience had heard that in the past 30 years, treatment has become much more effective. It has reduced mortality to an amazing degree. ‘This is why we argue about which to start, because we are fighting for our patients’ lives.’
On the other hand, it should be noted that the uptake of available therapies varies. The CHAMP-HF registry demonstrated for instance that in the US, treatment of HF patients is not sufficient; even ACEi/ARB, beta-blockers and MRAs are underutilized. Thus, there is lots of work to do. She concluded the debate by saying that ‘We all differ a bit in how we depend on the art and/or the science. For all, it is important to educate patients on where you’d like to go with treatment.’ Faster, is what the part of the audience wanted; as the final vote showed a shift to the PRO position, now with 60% of votes.