Ileana L Piña, MD, MPHD; John JV McMurray, MB ChB (Hons), MD


January 28, 2015

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Ileana L Piña, MD, PhD: Hello. I'm Ileana Piña and I am from Montefiore Medical Center in New York. I am here at the American Heart Association (AHA) sessions in Chicago, where it has been very cold. But inside these halls there is so much excitement. I haven't seen this much excitement at an AHA meeting for a long time. There are new papers, there are new trials being presented, there is new technology in the exhibit hall—we have all sorts of plans for really making this the go-to meeting.

And because of this, we are lucky enough to have Professor McMurray from Scotland with us. Professor McMurray has been the principal investigator (PI) for a very exciting trial called PARADIGM-HF.[1] In one of my previous blogs I talked a little bit about this new drug and this new type of drug. Because it's not just a new drug, it is a new type of drug that really uses the underpinnings of the pathophysiology of heart failure, with a better understanding of it.

So I have asked Professor McMurray to join me, and he has been gracious enough to grant us a little time. John, welcome.

John McMurray, MB ChB (Hons), MD: Thank you, Ileana, delighted to be here.


Dr Piña: Good to have you here. So, for our audience, can you just summarize PARADIGM-HF, and then we will get more into the discussion?

Dr McMurray: So PARADIGM-HF was a large, 8440-patient trial, comparing two treatments: the ACE inhibitor enalapril, 10 mg twice a day, and this new agent that you mentioned, an angiotensin receptor-neprilysin inhibitor, or ARNI, called sacubitril/valsartan, previously known as LCZ696.

Dr Piña: I think that is the name that everybody uses.

Dr McMurray: We compared these two treatments in patients with heart failure and reduced ejection fraction. The primary end point was cardiovascular death or heart-failure hospitalization. The trial was stopped early on the recommendation of the data safety and monitoring board [DSMB] after a meeting at 27 months because there was a highly statistically significant 20% reduction in the primary end point in the two components of that composite, so in both cardiovascular death and heart-failure hospitalization. Even overall mortality was reduced by 16%, and remember that is compared with an active treatment that itself reduces mortality.

Dr Piña: So what was the annual mortality, in general?

Dr McMurray: The annualized cardiovascular mortality rate was 7%, approximately.

Ejection Fraction

Dr Piña: That sounds about right for an NYHA class 2–3 population. I know in HF ACTION,[2] it was about 5% for class 2 patients and I think 12% for class 3. How did you define heart failure with reduced ejection fraction [HFrEF], how much ejection fraction?

Dr McMurray: Well, we stared with an ejection fraction of 40% or less. That was subsequently reduced to 35% or less.

Dr Piña: Why did you do that?

Dr McMurray: Because during the trial the EMPHASIS[3] heart-failure study was reported showing that the mineralocorticoid-receptor antagonist eplerenone was beneficial in patients with milder symptoms, so we recommended to our investigators that they think about using that. We realized that that might reduce our event rate, so one way to keep the event rate up was to reduce the ejection fraction. But we still had just under 1000 people in the range 35% to 40%, and if you do an analysis by tertiles of ejection fraction the treatment effect is the same.

Dr Piña: It might be interesting to see in >40% what is going to happen. As you know, we are doing PARAGON, which is the [heart failure with preserved ejection fraction] HFpEF trial.

Dr McMurray: Yes, that's right, yes.

Questions of Dose and Dosing

Dr Piña: A couple of other questions: What is the dose of valsartan in the drug itself?

Dr McMurray: That is a very interesting question, because the molecule LCZ696 is six molecules of the neprilysin inhibitor, six molecules of valsartan bound together, but it is an anionic form of valsartan, different from the valsartan that we use in the Diovan formulation.

Dr Piña: Like Val-HeFT.[4]

Dr McMurray: Like Val-HeFT, so it is 103 mg of valsartan that is in the 200-mg dose of LCZ696. But that gives plasma levels about the same as 160 mg of regular valsartan.

Dr Piña: Is it bid or is it qd?

Dr McMurray: Twice daily.

Dr Piña: So bid, and the dosing eventually, then, is equivalent to the Val-HeFT dosing, which is 160 bid.

Dr McMurray: Correct. And the back story here is that is why we went straight to phase 3 with this drug because we had to give the equivalent of 160 mg twice a day valsartan for the reasons that you have outlined. Because this molecule is made in a fixed 1:1 ratio, there is only one dose that we could use, which was 200 mg, and fortuitously the 97 mg of sacubitril (the neprilysin inhibitor in that 200-mg molecule) gives about 90% neprilysin inhibition.

Dr Piña: Wow, and pretty well absorbed? Regardless of food or whatever? You know, because some of the ACE inhibitors you can't give with food.

Dr McMurray: No. There is no issue about that.

Why Enalapril?

Dr Piña: How did you pick enalapril 10 bid as its comparator?

Dr McMurray: We had a lot of discussion, as you can imagine. There is only one ACE inhibitor that has been shown to reduce mortality in placebo-controlled trials, and that is enalapril. There are two studies, CONSENSUS-1[5]

Dr Piña: But that was 20 bid.

Dr McMurray: And CONSENSUS-1 was 20 mg bid. We were lucky enough to have Karl Swedberg on our executive committee, who reminded us that only 22% of patients in CONSENSUS could tolerate 20 mg bid. In fact, only 46% of patients could tolerate 10 bid in the SOLVD[6] treatment trial. SOLVD was the larger, more representative trial, so that is why we used it, but of course we were warned by the regulators that we had to ensure that patients in our enalapril group received at least the average dose that was achieved in SOLVD treatment.

Dr Piña: I am a heavy enalapril user in practice because we have gotten accustomed to it. It is a drug that I know well.

Dr McMurray: Same here.

Dr Piña: I know how it is absorbed and my target is usually 20 mg bid, and I get most patients to 20 mg bid. I think we have learned a lot since CONSENSUS—I talked to Karl about this—drop the diuretics a little bit, you can't blast them with it, and other little tricks of the trade, as I call them.

Dr McMurray: Well, I will tell you two interesting things. The first is that the average achieved dose in CONSENSUS was 18.4 mg a day. Our achieved dose was 18.9 mg a day.

Dr Piña: It is almost the same.

Dr McMurray: And the other thing is if you look at the more recent trials where there is forced titration of enalapril, so CARMEN[7] and CIBIS-III,[8] which was a strange trial that looked at starting a beta-blocker or an ACE inhibitor first and then taking both together. In both of those more recent trials where beta-blockers were being used in everybody, the average achieved dose of enalapril was only about 15 mg—so you do very well.

All About ARNI

Dr Piña: That's the tricks of the trade from 20 years of doing it. Tell the audience a little bit more about ARNI, because it is such a novel concept. Many of us remember omapatrilat.[9] Tell our audience what ARNI does and doesn't do.

Dr McMurray: So this drug does two things; it is a neprilysin inhibitor. We have talked about that. Why do we want to inhibit neprilysin? Well, neprilysin is an enzyme that breaks down a number of vasoactive substances. The best recognized of those are the natriuretic peptides, and you and I know that natriuretic peptides are our endogenous defense against volume overloads.

Dr Piña: And a very early defense.

Dr McMurray: Yes, so it makes sense that if you could figure out a way to augment natriuretic peptides, that might be a good thing if sustained in heart failure. You can do that by inhibiting the enzyme that breaks them down, but then why the angiotensin-receptor blocker [ARB]? Well, the reason for that is that neprilysin also breaks down angiotensin-2, so if you took a neprilysin inhibitor on its own then you would have a potentially detrimental effect of increased angiotensin-2.

So then you might say to yourself (and we have said that as you pointed out), why not block the angiotensin system using an ACE inhibitor, why an angiotensin-receptor blocker? And, of course, you alluded to omapatrilat, and that reminded us that both neprilysin and ACE [inhibitors] break down bradykinin and, of course, that caused angioedema—frequent and serious angioedema. So this molecule was engineered to get around that problem, block the renin angiotensin system with an ARB rather than an ACE inhibitor and hopefully avoid angioedema. That is why the molecule has those two parts to it.

What About Biomarkers?

Dr Piña: What if the drug gets approved and we start using it, what can we expect of [brain natriuretic peptide] BNP and [N-terminal probrain natriuretic peptide] NT-proBNP? Of course, we have a campaign—and it is in the guidelines, to look at the BNP and to look at the proBNP and try to adjust your treatment. Our audience has heard it before from me. We are doing a [National Institutes of Health] NIH trial of targeted therapy (GUIDE-IT), so what can we expect of the biomarkers? I know you have looked at this in the trial.

Dr McMurray: That is a very good question and one that gives an interesting answer, because what we found was that NT-proBNP is reduced but BNP is increased. Now, that dissociation between those two B-type natriuretic peptides seems strange at first sight, but you have to think back to the physiology. So when your left ventricle and your myocardium is stressed, when there is increase in diastolic-pressure wall stress, the myocytes produce proBNP. And, as we know, proBNP is cleaved in two in the plasma: the inactive N-terminal fragments (which is not a substrate for neprilysin) and the active C-terminal fragment, BNP, that we can measure and that is cleaved by neprilysin. You can think of BNP as a marker of the pharmacological direct action of the drug.

Dr Piña: Right. It is the effect of the drug.

Dr McMurray: But NT-proBNP is just an indirect marker telling us that this drug reduces wall stress.

Dr Piña: That the wall stress is coming down.

Dr McMurray: So NT-proBNP goes down, BNP goes up. But you do raise a very interesting question: in the future will this mean that maybe BNP will not be useful for monitoring patient progress and we will have to use NT-proBNP?

Dr Piña: Some labs may want to do both. They may want to do the point of care and double-check, which is, of course, a bit more expensive. What our audience also needs to understand is that the job of the natriuretic peptides is natriuresis, but they don't work even when elevated. How high did you see the BNPs go up?

Dr McMurray: BNPs went up modestly, I would say, by about 20%, but we measured only BNP because that is a more stable natriuretic peptide. Actually, [atrial natriuretic peptide] ANP is the better substrate for the enzyme.

Dr Piña: That's interesting.

Dr McMurray: And even [C-type natriuretic peptide] CNP is a better substrate, so we measured BNP for convenience. What we also did was we measured urinary cyclic GMP; as you know, cyclic GMP is the second messenger for all of these natriuretic peptides, and there was a striking increase in that. BNP was a more convenient measure to just see the pharmacological effect of the drug. And in case it is of interest, we also measured troponin, which was reduced significantly by LCZ696.

Dr Piña: Well, the wall stress, you would expect that should happen if it is consistent. Did you see a high urine output on the patients if the BNP went up and was actually now effective in the kidney for natruresis?

Dr McMurray: Good question. We did not measure urine revolumes.

Diuretic Dosing

Dr Piña: Was there a change in diuretic dosing during the trial?

Dr McMurray: Yes. You are always one step ahead. Over the course of the trial—some patients were in the trial for up to 5 years —we saw less diuretic use in the LCZ696 group than the enalapril group, so you are spot on in your prediction.

Dr Piña: You know, diuretic sparing is something that I try to do in my hospital practice, getting patients off diuretic gradually. I want them euvolemic, but I obviously don't want them hypovolemic, and I have found that if I can play with the renin angiotensin system and drop the diuretics, patients are much happier because they hate their diuretics and having to stop everywhere to go to the bathroom.

Dr McMurray: I completely agree.

Dr Piña: Tell me about potassium, how did the potassium behave?

Dr McMurray: One of the prespecified safety end points we had was development of hyperkalemia and we set two thresholds: 5.5 mEq/L or above 6.0 mEq/L, and we were anxious because any drug that lowers blood pressure has neurohumoral effects and raises concerns about hyperkalemia. In fact, we found that hyperkalemia, serious hyperkalemia, potassium above 6.0 mEq/L, was significantly less in the LCZ696 group.

ICD Use Much Higher in US Patients

Dr Piña: One last question about [implantable cardioverter defibrillators] ICDs. Every time we have done trials across the pond, there are fewer devices in Europe, more devices in the US. Was that the case here?

Dr McMurray: You are absolutely spot on again. A remarkable difference, I would say. In the US, 60% of patients had an ICD and for the rest of the world it was only 12%.

Dr Piña: What a difference! And it makes you wonder why.

Dr McMurray: I have no idea.

Dr Piña: I have no idea, either, but it is a very striking difference and it is something we have seen time and time again. We saw this in the WARCEF trial[10] and we wondered about the difference in sudden death. Did you see any difference in the US population of sudden death?

Dr McMurray: I don't know that we have done that specific analysis, we have done a couple of analyses that are relevant to the question. So we have looked at the effect of LCZ696 in patients with an ICD and those without an ICD and the effect of LCZ696 on cardiovascular mortality, so not specifically sudden death. Cardiovascular mortality is identical, so there is over a 20% reduction in CV death even in people who have an ICD. We have also done a regional analysis, and there is an equally or even maybe slightly more favorable effect in North American patients than patients in the rest of the world.

Dr Piña: That is interesting. I am sure that you are going to look at sudden death at some point because you have the adjudication committee—

Dr McMurray: We have looked at it, yes.

Dr Piña: And hopefully we will see other papers. So two new papers, one in Circulation[11] and the other in the European Heart Journal.[12] Thank you so much for joining us.

Dr McMurray: My pleasure.

Dr Piña: This has been very exciting. I look forward to more work on this drug and more publications on this novel concept of heart-failure therapy.

Pretty soon the PARAGON trial will be starting, which is the HFpEF part of this drug, an area [in which] we have no treatment. We will be doing PARAGON in New York, and I have total equipoise because I have no idea what to do with these patients.

Thank you for joining me today. This is Ileana Piña signing off.


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