COMMENTARY

The Case for Adherent Early Adoption of Entresto

Seth Bilazarian, MD

Disclosures

August 03, 2015

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Follow the Trial, Not the Label

Hi. This is Seth Bilazarian, for Practitioner's Corner on theheart.org on Medscape.

I want to do a brief review on Entresto™, the new angiotensin receptor-neprilysin inhibitor (ARNI). I was going to call the review "Early, Strictly Adherent ARNI Adoption." I thought that was a better title than "Is Entresto or LCZ696 Valsartan, Along With the Neprilysin Inhibitor Sacubitril, an Immediate Paradigm Shift for Your Systolic Dysfunction or Heart Failure With Reduced Ejection Fraction (HFrEF) Patients?" I thought that was not a very good title, so we will go with "Early, Strictly Adherent ARNI Adoption."

As I blogged previously, I don't think there is any virtue in early or late adoption for our patients. We try to adopt new drugs and procedures in an appropriate time frame and in appropriate patients, but late adoption isn't virtuous, in my mind, either.

If we are early adopters, however, we really need to be strictly adherent to and emulate trial use. We have to observe the inclusion and exclusion criteria that were set up by the trialists, and follow the strategies for drug initiation and limit doses to those studied by the trialists. We need to be very strict about that, and that is what I meant when I said "strictly adherent." We should really try to follow the trial outline, not the US Food and Drug Administration's (FDA's) package insert.

What I am referring to there is that when we had the RE-LY[1] trial of dabigatran in atrial fibrillation, there were doses of 150 mg and 110 mg in the trial—but then the FDA approved the drug at a dose of 75 mg, which was never tested. That makes no sense to me; we should stick to the trial.

Of course, this ARNI drug has a reported 20% reduction in cardiovascular death or heart failure hospitalization. The number needed to treat was 21 to reduce that composite endpoint of cardiovascular death or hospitalization at 27 months. The number needed to treat was 32 to prevent 1 cardiovascular death at 27 months. The curves separated early and were diverging at the end of the trial, not only for the composite endpoint but also for the individual components.

This dual-inhibition idea is biologically plausible, blocking the vasoconstrictor effects of the renin/angiotensin system with the angiotensin receptor blocker (ARB) and using the neprilysin inhibitor to enhance vasodilation by reducing the degradation of peptides. That is worthy of seriously considering using this drug.

John Mandrola has blogged on 10 reasons for caution with this drug. When I read John's "slow medicine" piece, I came away with the idea that he is really recommending that this not be adopted. Maybe that wasn't his intention, but that is the flavor of it to me by giving 10 reasons to be critical of the PARADIGM-HF data.

Blogger Rebuttal

Let me just briefly review those. I strongly urge you to look at both the paper[2] and at John's piece, called "The Benefits of Slow Medicine Apply to Entresto."

First, he says that enalapril was really an inadequate comparator that it was a straw man, and I don't think that there is any basis for him to say that. Enalapril 10 mg twice daily (bid) as a goal dose was what was done in both the CONSENSUS trial[3] and the SOLVD trial,[4] and the achieved dose in those two trials that showed that enalapril was superior to placebo was actually lower than the dose achieved in PARADIGM-HF. The average daily dose achieved in this trial was 18.9 mg, and in those older trials, it was slightly less. So I don't think that is a legitimate criticism.

John's second criticism is that the run-in phase caused a number of patients to drop out, and there is no active run-in phase for patients in the real world. I think it is correct to worry about a run-in phase that really can exaggerate the tolerability.

The way run-in phases work is that patients go into the trial, and if they can tolerate the drug for some period (in this case, 30 days), then they are allowed to proceed. If they don't tolerate the drug in the 30 days, then they are kicked out and they are not counted in the trial.

I think that is a legitimate criticism, but it is not unique to this trial. HPS2-THRIVE,[5] the study of niacin for lipid-lowering effects, used a run-in phase; it is very common strategy. The numbers that withdrew are important to consider, but the numbers that withdrew were equal in the enalapril arm vs the active comparator (ARNI) arm [Editor's note: The proportion of patients who withdrew from the study because of adverse events was higher during the enalapril run-in period than during the LCZ696 run-in period, after adjustment for the longer duration of LCZ696 exposure.] I don't think that is a legitimate criticism.

The other thing is that the run-in phase began with enalapril for 2 weeks and then 1 month of the ARNI drug. If you couldn't tolerate the enalapril, you weren't allowed to participate, either, and there may have been patients who couldn't tolerate enalapril who might have tolerated the ARNI inhibitor. That is a theoretical issue.

A third criticism John brings up is that this was a selected group of young patients. The mean age was 63 years, 80% were male, and nonwhite patients were underrepresented. That is certainly a legitimate point. Obviously, we need to have trials that involve more women and more minority groups. Fortunately for this trial, however, the underrepresentation of black patients was serendipitous, because we found that black patients had a greater risk for angioedema—a significant adverse event.

John's fourth criticism was that the absolute difference in death rate was 2.8% during the trial. In his words, that translates as "97.2% of patients experienced the same result. They did not die." That is probably correct, but I think that is not an accurate way to look at it, which I will come back to in a second.

The death rate in this trial was 17% vs 19.8% for all-cause mortality alone, but it was 13.3% vs 16.5% for cardiovascular death. If we tell our patients that they have a 1 in 5 chance of dying at 27 months if they are in this kind of patient group—these heart failure patients—most of them would not consider that a low risk.

John says that the PARADIGM trial was terminated early. That is certainly always a concern in these trials, but 27 months of therapy and diverging curves and really no crossover in the first 27 months is pretty reassuring.

John's sixth criticism is that more than 1000 centers randomly assigned patients in the PARADIGM-HF, trial and this requires a lot of quality control of the raw data. I don't really understand that criticism at all. For instance, if we look at the three first trials of novel oral anticoagulants (NOACs), there were 951 centers in RE-LY,[1] 1178 centers in ROCKET AF,[6] and 1004 clinical centers in ARISTOTLE.[7] Lots of trials have very large numbers of centers and do a good job with data collection.

John's seventh criticism is that more patients in the ARNI group experienced low blood pressure; of course, that is a concern, but we have to keep the side effects in context. Yes, there was more low blood pressure in the ARNI group compared with the angiotensin-converting enzyme (ACE) inhibitor group, but there was less hyperkalemia, less renal impairment, and less cough with the ARNI. So like everything, there are risks and benefits, and there were certainly fewer adverse effects in some areas.

John raises an eighth point that there may be off-target risks to this that we don't know about. We have certainly seen that with statins and cholesteryl ester transfer protein (CETP) inhibitors, so that is something that is concerning—but again, we have to put that in context. We have a disease that is killing one fifth of patients at 27 months, and moving the ball forward with better therapies may be important.

John also brings up the concern about cost, which I will address in a second. And John's final comment, his tenth criticism, is he is worried about distraction—that physicians like us will be distracted and spending time talking to our heart failure patients about the ARNI therapy. I have to say that this is not a legitimate criticism, because it is one of the few things that we can do and no one else can do. We can't outsource the important issue of discussing trial data and how they affect patients, and how they should be interpreted by patients to help them make the best decision. Shared decision-making is the only thing that we can't outsource.

We have to talk to patients about nutrition, but we can outsource nutrition counseling. We certainly can talk to patients about lifestyle changes, but some of that can be outsourced. We are supposed to spend time contextualizing these data and helping patients understand them and make good decisions.

Back to the Death Rate

How do we handle the 2.8% absolute risk reduction in death with regard to shared decision-making? There is a lot about hazard ratios, relative risk reductions, absolute risk reductions, and number needed to treat that can be very difficult for patients to understand, and can be used in many ways to almost manipulate patients. We have to be cautious of that.

If we are going to be consistent, let me use patients with atrial fibrillation as an example. We would say that at a CHADS2 score of 2, the risk for a cerebrovascular event is about 4% annually. Vitamin K antagonists lower that rate about 60%, to 2.4%. That is an absolute risk reduction of only 1.6% in stroke, not in mortality, but we all agree that oral anticoagulation is appropriate in stroke patients with a CHADS2 score of 2 or greater. Now you can also say that 99% of the patients have the same outcome, as John said, but I don't think that is helpful for patients to understand it.

Statins, of course, could never be recommended for primary prevention because there is no mortality benefit if we use the current atherosclerotic cardiovascular disease (ASCVD) risk estimator cut-off of 7.5% at 10 years, or a 30% reduction in relative risk reduction over 10 years. That would be very difficult to justify if you don't believe that 2.8% mortality benefit in the PARADIGM-HF trial is big enough.

We have the PROVE IT study,[8] which lowered the event rate from 26.3% to 22.4% but without a statistically significant mortality benefit, and we routinely use atorvastatin instead of pravastatin in our post-acute coronary syndrome (ACS) patients.

And then, finally, with implantable cardioverter-defibrillators (ICDs) in the MADIT II trial,[9] the mortality benefit was 19.8% vs 14.2%—a 5.6% absolute risk reduction. We could argue that 94.4% of patients had the same outcome. We could also argue that 81.9% of the patients without a device survive regardless of therapy. But we can also say that number needed to treat was 18 to save a life, and I think that is what has driven us to say that this is an appropriate, reasonable therapy.

So the benefit of the ARNI, in my mind, is that there is an 18% relative risk reduction with enalapril compared with placebo in these patients with systolic dysfunction heart failure, and on top of that, another 20% reduction. If you believe in enalapril and accept the magnitude of effect, then you really should believe in this therapy.

The cost of the drug, of course, is going to be very important. The cost has been said to be $12.50 per day—over $4000 per year, a really dramatic difference compared to what patients pay for ACE inhibitors. Patients can get ACE inhibitors at $10 for 3 months or $40 per year, so we are talking about hundreds of dollars in greater expense.

But there may be some things afoot. It has been reported by the Wall Street Journal and Reuters that Novartis is approaching payers and strategies to have a discounted price that would then result in a payment back to Novartis if there are good outcomes in terms of reductions in hospitalizations. Novartis is also considering options to help physicians monitor patients with outpatient monitoring to help prevent heart failure hospitalizations.

Those are potentially important things that may be different. And it is a win/win for both the industry and the manufacturer to produce sales of this drug, but also for patients and payers—and, of course, for physicians, if they are willing to put their money where their mouth is.

Who Do You Start With?

One advantage of this therapy is it is not an add-on heart failure therapy. It is a replacement therapy. It will be a fastidious transition from the ACE inhibitor; the package insert (as done in the trial) requires patients to be off an ACE inhibitor for 36 hours before beginning the neprilysin inhibitor because of the risk for angioedema.

This is going to take a lot of care by us in asking patients or families to go through the house and find ACE inhibitors and put them away, or discard them to make sure that they are not used in combination by error and therefore increase the angioedema risk.

And, of course, many of these patients are feeling quite well. They are stable heart failure patients—class II. Convincing them of a therapy that has a mortality benefit may be difficult, and they may be content to just stay with what they are doing. It is always something that is a challenge about how we enroll new patients.

Who should we start with? I am going to start with clinically stable HFrEF patients. That is who the trial studied—patients with largely class II or III heart failure (70% were class II patients). The ejection fraction was originally 40% but was amended to less than 35%, and the trial required the patients to have an elevated brain natriuretic peptide (BNP) level > 150 pg/mL or a pro-BNP level > 600 pg/mL.

During the trial presentation, the authors said that they don't think we should use BNP level, but this was a requirement of the study, so I think it is reasonable to use these markers. They excluded patients with systolic blood pressure < 95 mm Hg and excluded patients with potassium levels > 5.4 mmol/L, and they excluded patients with a history of angioedema—so of course we should exclude patients with all those things.

And when I look at the box plot of subgroup analysis, I see that it seems that patients with ejection fractions < 35% had superior outcomes with the ARNI, whereas the confidence intervals for those with ejection fractions of 35%-40% embraced unity. Patients with prior use of ACE inhibitors seemed to do better. Patients with class I or class II heart failure seemed to do better with the drug than patients with class III or IV disease. White patients did better than patients of other races, and patients younger than 75 years did better than older patients. At least initially, these might be patients who would be better to start with, to get our initial experience.

I am going to start with those patients, and I am going to spend a lot of time teaching them about the 36 hours off an ACE inhibitor, because I am really trying to enroll families, sons, daughters, and spouses to get the therapy out of the house. Not taking ACE inhibitors for 2 full days would be probably a better strategy than 36 hours.

The recommendation is to start at the 100-mg dose and titrate up to 200 mg, but my approach will probably be to start with an even lower dose of 50 mg to be extra-cautious. One of the other things that is going to be important to keep in mind is that the neprilysin inhibitor prevents the degradation of BNP; those people who believe in BNP guidance will be at a loss, because BNP levels will be naturally higher on this therapy.

In conclusion, I am going to be an early but very cautious and strictly adherent adopter of ARNI therapy, if I am allowed by my pharmacy benefits managers. If John Mandrola's idea of slow medicine is similar to slow cooking, in which we approach it very carefully and we put a lot of care, thought, and experience into the approach to try to get the best-tasting meal, then I am completely in agreement with him. But if slow medicine means that with all those 10 cautions he presented, we really should avoid this drug altogether, then I am in disagreement, because I think this is a novel and important therapy that is going to be very useful, and if we get experience, we will be able to appropriately adopt it.

Until next time, I am Seth Bilazarian. Thanks for listening.

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