COMMENTARY

We All Have Hearts -- Let's Help Them Work Better and Longer

Henry R. Black, MD; Jeffrey S. Borer, MD

Disclosures

June 09, 2016

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Henry R. Black, MD: Hi. I'm Dr Henry Black, an adjunct professor of medicine at the Langone New York University School of Medicine. I'm here today with my friend and colleague, Dr Jeff Borer. Jeff, welcome.

Jeffrey S. Borer, MD: Thank you very much, Henry. I'm happy to be here. I am a professor of medicine as well as cell biology, radiology and surgery at the State University of New York Downstate Medical Center, where I spent many years as chief of cardiology and chairman of medicine. I have now given up those administrative roles to direct two research institutes. I am also an adjunct professor of cardiovascular medicine in cardiothoracic surgery at Weill Cornell Medical College of Cornell University, where I had been on the full-time faculty for 30 years before moving to Downstate.

The Most Important Questions in Clinical Cardiology

Dr Black: You are one of my go-to guys for a question like this: What do you think are the most important questions in clinical cardiology right now?

Dr Borer: That's a wonderful question, and one that is very difficult to answer. I think that the key-issue question is how to help people with coronary artery disease, because that is the most common cardiac problem. We know that there are several risk factors, which you spent much of your career studying, that will definitely affect the likelihood of disease-related endpoints like death, heart attacks, and hospitalizations.

It's not clear how best to deal with people with coronary artery disease, but certainly the new kid on the block that is most exciting right now is the PCSK9 inhibitor. PCSK9 inhibitors hold the potential for lowering LDL cholesterol far beyond what we have been able to do with conventional drugs. A PCSK9 inhibitor is a "biological," not a conventional drug. It is self-injected, not swallowed, so it's a little bit harder to use than most conventional drugs, but it's very effective. My guess is that it will change the way people with coronary disease are treated.

Heart failure is probably the second largest problem that we face. The major issue right now is how to treat patients with systolic heart failure so as to incorporate all of the new information we've developed over the past couple of years. Two new drugs were approved by the US Food and Drug Administration (FDA) in 2015. We don't know exactly how to use them together or even if it's appropriate to use them together—though, theoretically, co-administration should be possible.

A third problem is how to treat people with hypertension. Having worked with noted clinician-researcher John Laragh, MD, for many years, I believe that there are some approaches that work better than others. It's not just about getting the blood pressure down. I think mechanism-specific therapy may be important. More effort in that area is necessary.

Another important area, on which I've focused much of my professional life, is heart valve disease. We now have catheter implantable heart valve substitutes that have to find their way into the therapeutic armamentarium. The current issues involve identifying the patients who should receive these devices rather than conventional surgery. How severe must the illness be before a patient should no longer be considered a candidate for conventional surgery for valve replacement? That has to be worked out, and the only way to work it out is with data.

A sub-issue of the catheter-based heart valve implantation problem is the issue of valve-in-valve re-replacement procedures. What do you do with valve failure in somebody who has already had a valve implanted, either surgically or by catheter? We know that it's feasible to replace the valve by inserting a new valve via catheter into the stent that was the infrastructure for the previously implanted valve. However, we don't know when to do it, which is a big problem.

In order to understand how to deal with valve-in-valve, one has to know a fair amount about the valve that will be the recipient of the new valve as well as the characteristics of the new valve to be implanted. That information isn't readily available. It's not understood by most cardiologists that the characteristics of the recipient valves are patent-protected. So, the companies that make those valves don't have to provide that information. If they do not, it is very hard for the operator who wants to implant a new valve, because he or she won't know what can reasonably be done to put a valve into another valve.

There are many other issues that one could raise, but those four are pretty major issues.

The Need for Preventive Cardiology

Dr Black: Let's talk about hypertension. One of the things that I find interesting in cardiology, especially when discussing lipid disorders, is the issue of residual risk, which implies that you can lower the risk for a heart attack or related events to zero. We never think that way in hypertension. We are learning more about the right goal, and both the SPRINT trial and the HOPE-2 study are helping to answer that question. We're getting more and more information, but it looks as if we need to create someone that I believe in but haven't seen, which is a preventionist—the opposite of a hospitalist.

We ought to have people who are trained very well in the techniques of prevention, whether it's salt, exercise, lipids, or whatever. That is a whole specialized area that has been somewhat neglected. It's not as lucrative as doing surgery, perhaps, but if we can prevent those diseases, we can put surgeons out of business. That is not something I'd want to do, of course. We need them. But I think we also ought to focus more on prevention.

As far as mechanisms [for control of hypertension] go, I think prevention would certainly be the best way. The renin-angiotensin system has been studied since John's first idea. I'd never disagree that there were characteristics of individuals that could be defined by [other] mechanisms. However, I think that we've probably gone as far we're going to with [study of the renin-angiotensin] system. Aliskiren, for example, has been a disappointment. Just about every study and clinical trial has fallen short. Blood pressure is still the most common population-attributable risk factor for heart disease. We're in the midst of an obesity epidemic. What do we do with adolescents and young people to keep them from gaining the weight that makes everything else worse? Do you have any thoughts about that?

Dr Borer: First of all, I agree completely that preventive cardiology is a very viable and important area. The first thing I did when I arrived at my current institution was to establish a preventive cardiology subgroup, believing that to be the best way to reduce the burden of coronary disease and the risk factors for events in patients with vascular disease. You ran a division of preventive cardiology in Chicago. It is a wonderful model and should be emulated elsewhere.

In regard to residual risk, it's interesting that even very well-read people tend to forget that hypertension really does carry more risk than hyperlipidemia. It's easy to forget because the impact on outcomes of changes in cholesterol and LDL cholesterol is dramatic and has been well demonstrated. That is also the case with hypertension, which was demonstrated earlier.

Dr Black: We started with clinical trials of hypertension in the 1960s, and many were completed before it was well understood how to best do a clinical trial, including issues of trial size and design. We've done incremental things since then. We still don't know what the best treatment is for everybody or what factors should lead to selection of one particular regimen compared with another.

PCSK9 Inhibitors: Will They Work?

Dr Black: I'm very interested in what you said about PCSK9 inhibitors. It's interesting that we spent so much time getting away from injections and now may be going back to them. Some pretty sophisticated and easy ways for people to inject themselves have been studied. But what do we know about compliance with these drugs? Are patients giving themselves these medications and storing them properly? Do they have a shelf-life? I'm very interested in the answers to these questions.

Dr Borer: That's a good set of questions. Unfortunately, we're too early in the use of PCSK9 inhibitors to answer them definitively. I can tell you that in the ongoing trials—I have to be careful of what I say because I'm the head of the Data and Safety Monitoring Board (DSMB) of one of the biggest ongoing trials—people seem to be pretty compliant. Whether they will continue when no longer involved in a trial is not known. Injection-site reactions are among the most common adverse events in people who take PCSK9 inhibitors, so there has to be a fair amount of pre-education about the benefits of lowering cholesterol that way, but I think that is doable. People don't complain very much about this kind of administration. And remember: Patients administer insulin and other drugs parenterally without great problems. I think it's going to work out okay. If not, and there is a problem, there are multiple technologies that are used in other areas to allow protein molecules to be masked somehow in the gastrointestinal tract so that they can be absorbed, detoxified, and get to where they're supposed to go. Research in that area may have to go on with PCSK9 inhibitors. At this point, however, it looks like parental injection is working.

Data and Safety Monitoring Boards vs Regulatory Agencies

Dr Black: You mentioned DSMBs. I've been very interested in discussing the recent challenges to the role of the DSMB raised by the European Medicines Agency (EMA). I know you have studied and written about this issue. What are your thoughts?

Dr Borer: The issue that you're alluding to was very difficult to resolve. Several colleagues and I made up the DSMB for a trial. Because we've written an article[1] about this process and the study[2] that was the focus of our article was published in the New England Journal of Medicine, I don't have to be too guarded with what I say. The study involved the use of aliskiren, which you mentioned earlier. The issue was that the regulatory agencies overseeing the aliskiren trials were privy to the same information as everybody else. Another trial—not one monitored by our DSMB—involving different populations and looking at different outcomes had some unfortunate occurrences. The regulatory agency said, "Hey, we're concerned about this. We want to see the data." And we said, "No, you can't see the data. If you see the data, the trial is over and the drug is dead, and that doesn't seem right."

We knew at the time that the data [in the trials we were monitoring] looked pretty good. In at least one of the two trials we were monitoring, at least in the population we were studying, the drug seemed to be working. It might not be as positive by the time the trial was over, but it looked like it was working [at the time of this EMA request]. If we released the data to the regulatory agency, the trial was over. That didn't seem fair to the sponsor, but most important, it didn't seem fair to the patients who could benefit from this drug combination if it actually did work the way it appeared to be working. So we said we wouldn't give the data to the regulatory agency, and the regulatory agency said, "Okay, then, we want all patients who have these characteristics that we think will respond adversely to this drug to be taken out of the ongoing trials and not entered ever again." And we said, " How about if we talk about this? This doesn't seem quite right." But no, that's the way it was. So the ongoing trials had to run for an additional year to recruit sufficient patients to be adequately powered to see something if it was really there. That's a big new hurdle.

At the end of the day, the trial showed a trend towards benefit that was not statistically significant. And it wasn't unreasonable for the regulatory agency to want to see the data. But looking at the data in an ongoing trial destroys the credibility of that trial.

Dr Black: Isn't that what a DSMB does—look at data?

Dr Borer: Yes, it is, indeed. What we suggested in our article was that the DSMB was, indeed, looking at these data on a continuing basis; we asked that they trust us to determine whether it is okay to continue.

Dr Black: We have to go through many hurdles to be qualified to be on the DSMB, so isn't that good enough?

Dr Borer: It should be. There was a fair amount of hostility involved, although much less than you would think. We understood the position of the regulatory bodies and they understood our position. At the end of the day, we decided that if this comes up again, and it will, we've got to suggest some remedies, some methods that would allow us to work this out.

Our suggestion, which was published in the New England Journal of Medicine, was that if a regulatory agency is concerned, it should be able to ask the DSMB for its statistical analysis plan. It should be able to ask how we're going to move forward and how we're going to make decisions. And this information should be written. That should remove some of the concerns that the regulatory agencies might have. We made that suggestion and the regulatory agency and the sponsor seemed to agree. It wasn't a tremendous hosanna, but we all sort of agreed.

Dr Black: But we have so-called stopping rules, which is important. As you get closer and closer to the rule, you may have to extend or meet more frequently. We did that with the ACCOMPLISH trial. We met in 3 months instead of 6, and then it was clear that we could go on.

Dr Borer: Yes. Remember, though, that the stopping rules aren't really rules but rather flexible guidelines. At the end of the day, the DSMB has to be free to make whatever decision it thinks is in the best interest of the patients, even if that means transgressing the stopping rules. An open forum with a regulatory agency to discuss the rules, the analysis, and data being monitored was suggested as a way forward, and there seemed to be agreement about that. If that is true, we'll see new DSMBs writing charters with those types of principles involved.

Dr Black: I think that would be helpful. Setting up a study, planning the analysis, writing it up, making sure it works, reviewing the information—it all entails a lot of work for the members of the DSMB. Do you have any final words about cardiology in the future?

Dr Borer: Only that we all have hearts. The better we can make them work and the longer we can make them work properly, the better off we all will be. There must be an ongoing focus on research to create new knowledge. It's the creation of new knowledge that allows us to move forward—not just practicing what we know but creating new knowledge.

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