Ileana L. Piña, MD, MPH

Disclosures

April 20, 2016

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Editor's Note: John J.V. McMurray, MD, BSc, MB ChB (Hons), professor at the British Heart Foundation Cardiovascular Research Centre of the University of Glasgow, and consultant cardiologist at Glasgow's Queen Elizabeth Hospital, is interviewed about the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE), which was a late-breaking clinical trial presentation at the 2016 American College of Cardiology (ACC) Scientific Sessions.

Ileana L. Piña, MD, MPH: Hello. I am Ileana Piña from Albert Einstein College of Medicine and Montefiore Medical Center in the Bronx, New York. I would normally say to you, "This is my blog," but I am here at the ACC national meeting in Chicago, where it is snowing. One of the most fun things that I do is interview my friends from all over the world about the work that they are doing, the studies that they will be presenting here—many of them late-breaking trials and many of them published simultaneously. And it is my pleasure today to see my friend, John.

John J.V. McMurray, MD, BSc, MB ChB (Hons): I am John McMurray. I work at the University of Glasgow in Scotland in the United Kingdom. I am a cardiologist with an interest in heart failure in particular.

Dr Piña: How many years have you been doing trials?

Dr McMurray: About 25 years. I'm getting old.

Dr Piña: Heart failure, for our audience, is one of those syndromes that really has done the best clinical trials in cardiology because we take what we learn and then we move it along to the next step and try to prove our hypotheses. Sometimes things we believe in are not what we thought they were when you actually do the good randomized controlled trial. And I think that is a great introduction to your trial, ATMOSPHERE.[1]

ATMOSPHERE: Hard to Beat ACE Inhibitors

Dr McMurray: ATMOSPHERE was a trial looking at an alternative approach to blocking the renin-angiotensin system. Of course, angiotensin-converting enzyme (ACE) inhibitors are the gold standards; they're very hard to beat. We had tried with angiotensin receptor blockers (ARBs) and failed.[2] And this time, we tried with a renin inhibitor, a direct renin inhibitor. Of course, there are theoretical reasons why that is an attractive tool to use because renin is at the start of the cascades, and a lot of the treatments that we use actually cause a reflex increase in renin. Renin itself may have direct effects that are detrimental. That may also be part of the reason why some patients have renin-angiotensin system (RAS) escape during chronic ACE inhibition.

Dr Piña: That's the reason for adding the ARB to the ACE inhibitor.

Dr McMurray: That is the theory, but, of course, the practice—as you quite rightly say—is to test that hypothesis in human beings, and we did that. Our trial enrolled 7016 patients.

Dr Piña: For today's standard, that is a big trial.

Dr McMurray: And we randomized them to one of three treatment arms, so we had our gold-standard control arm, which was enalapril. The target was 10 mg twice a day.

Dr Piña: Class II patients primarily?

Dr McMurray: Predominantly New York Heart Failure (NYHF) Class II and Class III. As I said, enalapril 10 mg twice a day or the new treatment, aliskiren; we used a 300-mg dose once a day, which gives pretty much equivalent suppression of the RAS, and then a combination arm. The important thing about this combination arm is that we give aliskiren on top of full-dose enalapril.

Dr Piña: So it was 10-mg twice-daily enalapril and then 300 mg aliskiren.

Dr McMurray: You and I have talked before about the ARB trials where we showed benefit of adding an ARB on top of an ACE inhibitor, but it wasn't full-dose ACE inhibitor. So we followed these patients for just over a median of 3 years.

Dr Piña: Which is an excellent follow-up today in our heart failure trials. Two years is usually what we do.

Dr McMurray: Correct. And about 2600 patients had a primary outcome event. The primary outcome was the composite of cardiovascular death or heart failure hospitalization.

Dr Piña: Our usual composites.

Dr McMurray: The bottom line is that we did not see any difference in efficacy between the three treatment arms, so the hazard ratio for combination therapy versus enalapril was 0.93 and the hazard ratio for aliskiren versus enalapril was 0.99.

Dr Piña: Can't get any tighter.

Dr McMurray: But we did see an increase in adverse events. We saw more hypotension and hyperkalemia with combination therapy. We saw more renal dysfunction with combination therapy.

Dr Piña: Doesn't that remind you of some other add-on trials?

Dr McMurray: It does, indeed. I think there are several important messages from this trial, but one of them is that there is a ceiling to RAS inhibition, and if you go above it, you get no more benefits. You just get more adverse events. And that ceiling looks to be, on average, probably 10 mg twice daily of enalapril.

I think the second important message is that our interpretation of the ARB trials has to now be that the benefit we saw of adding candesartan to an ACE inhibitor or adding valsartan to an ACE inhibitor in the heart failure studies was actually because those patients weren't on a high-enough dose of background ACE inhibitor treatment. Actually, VALIANT,[3] a post-infarct trial, and ONTARGET,[4] Salim Yusuf's trial in a broader spectrum of patients with cardiovascular risk, where an ARB was added to a full-dose ACE inhibitor and there was no additional efficacy—those findings reflected the truth.

Dr Piña: It keeps adding to our fund of knowledge. All of these years and we still don't know the system as well as we think we do.

Dr McMurray: We are getting close now. My own view is that there probably won't be any more trials looking at different RAS blockade approaches because of the ceiling that I mentioned. The other interesting thing is that one of the criticisms of another trial that we presented (and that we have talked about), the PARADIGM heart failure trial,[5] was that sacubitril/valsartan perhaps was better than enalapril because it was a more effective RAS blocker, but I think we can probably discount that now. I am now even more convinced that the incremental benefit in that trial was due to neprilysin inhibition and other actions rather than more RAS suppression.

Dr Piña: This is very interesting. A good dose of valsartan in that trial too.

Dr McMurray: Yes. It was a different formulation of valsartan (combined with sacubitril) and gave the equivalent of about 160 mg twice daily

Dr Piña: The Val-HeFT dose.[6] Although not all of the patients got there.

Dr McMurray: No, of course not.

ASTRONAUT and the Perils of Subgroups Analyses

Dr Piña: Tell me about the patients with diabetes in ATMOSPHERE.

Dr McMurray: That was a very curious—and in my experience—unprecedented problem in this trial. As you know, there was a trial called ALTITUDE,[7] which was done in patients with diabetes and chronic kidney disease. Aliskiren 300 mg once a day was added to background ACE inhibitor or ARB treatment. That trial was actually stopped early for futility, but also because there were more adverse effects in the patients with diabetes. That caused some regulatory concern. Then, more recently, there was another trial with aliskiren called ASTRONAUT.[8] ASTRONAUT was a trial in acute heart failure in which aliskiren was added to background ACE inhibitor or ARB treatment. In that trial, which was neutral overall, a subgroup analysis[9] was done which showed harm in patients with diabetes—more cardiovascular deaths and heart failure hospitalizations—but apparent benefit in the nondiabetic patients. Now, I don't know what you think about retrospective subgroup analysis—

Dr Piña: We have been burned many times.

Dr McMurray: On the basis of that analysis, the European regulators became so concerned about this drug potentially being harmful in patients with diabetes that they asked to stop the study drug in all diabetics in the ATMOSPHERE trial, which we did.

Dr Piña: How many patients with diabetes did you have?

Dr McMurray: We had just under 2000.

Dr Piña: That's a pretty good number.

Dr McMurray: We had more events in patients with diabetes in ATMOSPHERE than in the ASTRONAUT trial at the end of the day, but, of course, our trial only followed diabetics for an average of about 2 years, whereas the nondiabetics were followed for a median of almost 4 years.

Dr Piña: That is an incredible follow-up time.

Dr McMurray: That is why the trial went on for a very long time. But you were right about subgroup analyses burning us sometimes. The interesting thing was that when we looked at our diabetic subgroup (we had a lot of them and a lot of events), if anything, there was a trend in favor of combination therapy. We definitely didn't see any of the harm that had been suggested in the ASTRONAUT trial. So, once again, subgroup analyses are misleading.

Dr Piña: We learn our lessons. Every time we have done a large randomized trial and gone back and looked at subgroups, the patients with diabetes usually do better with the intervention. They have such high event rates. I am worried when I have a diabetic with heart failure because they just don't do well.

Dr McMurray: You are absolutely right. Obviously, it was just a trend and I am not trying to make anything of it, but it did completely refute that original finding.

Dr Piña: Are you going to publish that?

Dr McMurray: The ATMOSPHERE trial was simultaneously published online in the New England Journal of Medicine.[1] There will be some interesting commentaries because the data safety monitoring board was upset (I think that is the right word) that their responsibility to oversee patient safety had been usurped by this regulatory intervention. I understand that there may be some commentary[10] from them and also perhaps some regulatory response to that.[11]

Lessons for Practitioners

Dr Piña: I look forward to reading this. What would you say to the practicing clinicians in our audience who ask, "How does this apply to my practice? What should I do?"

Dr McMurray: The first thing I would say is that ACE inhibitors are remarkable drugs and very hard to beat. We have tried three times. We tried with ARBs in ELITE[2] and failed. We have now tried with the renin inhibitor in ATMOSPHERE[1] and failed. We did make one other attempt to beat an ACE inhibitor, and that, of course, was with sacubitril/valsartan in PARADIGM-HF,[5] and we actually succeeded. This reinforces the remarkable results of PARADIGM-HF, so my recommendation to physicians would be that, if you can, your patient should be changed to sacubitril/valsartan because they will do better. If you can't, then an ACE inhibitor remains the one to beat.

Dr Piña: And very inexpensive too. How important is it to add spironolactone?

Dr McMurray: Vastly important. The fact is that your best chance of being alive and well 6 months, 9 months, 1 year, 2 years, 5 years from today, if you have heart failure with reduced ejection fraction, is to be on a beta-blocker, a mineralocorticoid receptor antagonist, and sacubitril/valsartan. Those three drugs are all crucial. They all work in different ways. The benefit is additive. There is no question about that.

Dr Piña: The message to our audience: Spironolactone added to the background therapy has additional benefits with very few downsides, except for (perhaps) hyperkalemia, which we battle every day. Our heart failure patients are on so many drugs, and as we continue to pare down, we are coming down to three. But then there are patients with diabetes who are probably on insulin or some other drug, and many of them have chronic obstructive pulmonary disease, so they may be on inhalers. This is not a population without comorbidities, and I feel for you guys in practice because the patients leave the hospital—we know this; we have counted them—on 13 drugs, and by the time they have seen us at the first visit, we pare it down to eight. But I have a hard time getting below eight. We take away the sleeping pill and the stool softener and the laxative and the pain reliever.

Dr McMurray: I do exactly the same. Any time I think about introducing a drug, I always try to think about stopping one so that the patient's pill burden isn't increased.

Dr Piña: That's right. Make it easier for them if we can. I want to thank you on behalf of the heart failure world because, through the years—and we have known each other longer than we would like to admit—you have really looked at this from the scientific basis of step-by-step and learning more and more as we do these trials. I think it convinces me that subgroup analysis has its problems and that we really need to do the prospective, well done, well-controlled trials that will work. This is Ileana Piña, signing off.

Disclosures: John J.V. McMurray, MD, BSc, MB ChB (Hons), has disclosed the following relevant financial relationships:
University of Glasgow received payment for involvement in clinical trials and meetings related to the study treatments sponsored by: Novartis; Amgen; Cardiorentis AG; GlaxoSmithKline; Theracos, Inc.

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