Investigator Perspective: How Recent Clinical Trials Are Reshaping Treatment Paths in the Management of Heart Failure - A Q&A With Justin Ezekowitz, MD

AJMC^®: What are the current unmet needs within the treatment spectrum of heart failure?

Ezekowitz: One of the key unmet needs in heart failure with reduced
ejection fraction is reducing hospitalization by looking at both pharmacologic and nonpharmacologic interventions. What we often see is that patients are admitted to hospitals quite frequently. The unmet need is how do we reduce the hospitalization or ED [emergency department] visits, or symptomatic deterioration requiring IV [intravenous] diuretics. We are trying to find new therapies for when people are already on good medical therapy and have all the appropriate therapies on board. As we add in each therapy, we notice this unmet need remains. We keep reducing the risk of morbidity and mortality and improving quality of life, but it’s not back to normal. Heart failure is a chronic and challenging disease that requires pharmacological therapy and nonpharmacological therapy. The question is how do we organize care so [we have] strategies for follow-up, exercise, diet, etc, all those things around life that happen 24 hours a day?

AJMC^®: As an investigator on the VICTORIA trial (NCT02861534), can you talk about the significance of the inclusion of patients with recent hospitalizations for heart failure in the past 6 months?

Ezekowitz: The heart failure trials break down into 2 different styles, and VICTORIA is a wedge right in the middle. There are chronic heart failure therapy trials where people have had heart failure for some time, and they’re enrolled from outpatient clinics regardless of what has happened in the past 6 months, 12 months, 2 years of time. The other types of trials would be the acute heart failure trials, with the start of medication in the ED or the first days in the ward—run it through an IV, and see what happens afterwards. This one fits right in the middle, so if patients are in a hospital, even if they are on good therapy—which the patients in VICTORIA were—something has happened, they’re still at high risk, and we need to add something more. Individuals are at risk for those first 30, 60, 90 days, really up to 6 or even 12 months after a hospital visit, so the thought is there [has to be] an opportunity, or a window has opened, and you need to take advantage of it. Many of the US hospitals will be familiar with these 30-day readmission risk scores, and payment is related to that. This trial attempts to address some of that, by starting best therapies up front, right in the hospital or very early after the hospitalization. It tries to fit right into that wedge of those 2 different types of trials and enroll a higher-risk population rather than go for a lower-risk, but chronic and important, population.

AJMC^®: What impact do you anticipate this wedge approach may have on the managed care spectrum regarding management of heart failure?

Ezekowitz: From a patient’s perspective, it’s very easy to see fewer hospitalizations, better quality of life, living longer, etc; [it is] relatively easy to see how these things are advantageous to any group or patient. From a health system perspective, we’ve always focused on getting people out of the hospital very quickly, often to the patient’s detriment because they get readmitted quickly. That’s not good. In fact, that’s probably a more expensive strategy than it is to keep them a little longer and effectively treat them.

ED visits are very expensive proportionate to the time, whether a patient has been there 6 or 12 hours, so anything that reduces an ED visit or a hospitalization is going to be important from a health system payer perspective. Things like VICTORIA and other new medications do that, so you really want to be aggressive on the transition between the hospital to the outpatient world, and patients are at high risk sitting there, say, 5 months after a hospitalization. Why would you not want to reduce that risk of them being hospitalized, just from a health economics perspective?

One other tiny thing here is, if we’ve learned anything from COVID-19 [coronavirus disease 2019] or pandemics or epidemics, it’s that anytime you could give organized care that does not require a hospital, so you can create strategies around managing it, that’s going to be a win for a patient. Whether it’s seeing people by video or evaluating them with new technologies, whatever it might be, keeping them out of hospital is actually a really good strategy where it’s appropriate.

AJMC^®: What are some of the most important details regarding the findings in VICTORIA?

Ezekowitz: First of all, it’s important to note that VICTORIA is a positive trial overall, having met its end points for cardiovascular death and heart failure hospitalization reduction. This was powered to meet its primary end point, and it did. It was met without squeaking through with a few events; it had a very high event rate in terms of number of events from patients. There was high risk for both death and heart failure hospitalization, and when you look at the primary end point, you can see that it’s predominantly driven by heart failure hospitalization. That is because these people in the very short term, in under a year, are at a much higher risk for that than they are for cardiovascular death, which continues at about 11% per year. It’s not a low-risk disease where there is a 2% or 3% death rate per year. This is a high-risk disease.

The other point is that vericiguat was very well tolerated. You have a medication that does not require the monitoring of potassium and creatinine in an outpatient setting, which is a big win for patients, not having an extra blood draw with another medication start, which is a very common practice for most of our pills. It’s also the effects of the safety from a blood pressure perspective and other hemodynamic perspectives that clinicians worry about, which generally were well tolerated up to the target dose of 10 mg a day. Interestingly enough, the majority of people stayed on the therapy trial, which tells you that the persistence or adherence of the medication’s going to be likely high in clinical practice; a safely, well-tolerated medication means it’s probably going to translate well into practice. Other medications can be a little trickier to manage, so when we put this into perspective with other choices we have to make, vericiguat is going to be an easier one for people to use, similar to some of the other newer medications we’re also using.

AJMC^®: What do you think should be the next steps or future directions when it comes to further evaluation of the long-term benefits and safety of vericiguat?

Ezekowitz: In VICTORIA, we treated approximately 5050 patients and follow-up was about a year. The early preclinical data don’t show any unusual safety risks that we are aware of. Of course, any medication can do anything, so we have to be very aware to follow up, and there are pharmacovigilance groups that do that well. I think the implications are very much like when ACE [angiotensin-converting enzyme] inhibitors came out in the 1990s for heart failure. It was a long time ago, but it took a while for the clinical community to adopt and feel comfortable using them. I think it’s going to take a while for people to adopt a new medication. We need to get over that hump, so we need to do everything we can to do that. We have now 5 medications, so I call it 5-alive, maybe 6 soon: 6 classes of medications that reduce morbidity and mortality, so [being] selective with those is going to be a trickier goal for a clinician. Safety is not the concern for vericiguat, but I think something we always think of in clinical practice is which medication for which patient, and that’s the trickier question that’s harder to answer based on the trials.

AJMC^®: Do you think there’s a relationship between the number of mechanisms and the reluctance, or the broader hesitation, of people to adopt newer things?

Ezekowitz: One of the challenges is that we always want to say this 1 drug does it all, but we have to attack multiple different parts of the pathway that really reduce the risk. There are 5 or 6 different lines of pathways you need to interfere with, so it’s not a surprise we have to interfere with all of them to some degree. For some patients, interfering with one pathway more than another might be more important. The key is there are lots of things going on, so why would you not take the opportunity to hit all of them in a slightly different and tolerable way?

AJMC^®: Can you talk about the broader trial landscape for heart failure, with respect to newer directions in care?

Ezekowitz: DAPA-HF (NCT03036124) and PARADIGM-HF (NCT01035255) are well-done trials with positive outcomes that enter into practice, so that’s really straightforward. As a clinician, I use the results of those on a daily basis, so I’m happy to see those. It’s nice to have scientific competition, but from a patient perspective, it is a fantastic opportunity. We’ve got an opportunity in a clinical practice/setting to say, “Hey, we’ve got this big bucket of choices of medications. We’re going to start here and then move forward, and we can do that because we have some backups.” Backups can be added in actively, but what an opportunity as a patient, knowing it’s not just 1 drug, and that’s it.

The nice part about DAPA-HF is that it evaluated an easily tolerated medication (dapagliflozin) in lower-risk population—and it still has a pretty striking benefit for patients. That’s a great way to think about the DAPA-HF population. It is lower risk overall for clinical events, but the low risk doesn’t mean no risk, and I think that’s hard sometimes for people to accept, as the low risk still is a much higher risk than our average day-to-day lives or any patient with coronary disease. This is high risk in other populations but low risk in the heart failure scheme of things.

The PARADIGM-HF trial used direct active comparator, which is a nice design for a trial. It’s taken a while for people to adopt it here in Canada. The uptake is slow because of things around payment—reimbursements, availability, you name it—and then there’s clinician inertia. The question clinicians ask are, “Can I use this medication with this patient right in front of me based on payment, reimbursement, a form to fill out, a preauthorization? Can I get them 30 days’ or 90 days’ worth of medication?”

AJMC^®: Given the number of mechanisms available to treat heart failure, why do you think uptake can be slow for newer agents?

Ezekowitz: The clinicians are probably the biggest hurdles, and I don’t mean that in a negative way. There’s a lot going on: disease, patient education, research. I spend a fair amount of my time doing that in terms of clinician education. One of the challenges is there’s a bit of inertia, as it takes a bit more time to do something than to do nothing, even though they are good physicians and clinicians.

The second part is that they’re worrying about risk. Clinicians are usually risk-averse and safety conscious, so I think for some of the medications we’ve had, there’s a risk of safety concern “X” or safety concern “Y,” and they will equate that with not starting because of that. That is a bit of a challenge in clinical practice. We have medications that can be added in easily without the usual risks, and I point to vericiguat as an example, which has no hyperkalemia. Other medications may cause hyperkalemia, and even though I’m comfortable with it, not every clinician is with hyperkalemia, so people just don’t use that medication as often.

When we’re thinking about medications and uptake, part of it has to be about safety and getting people over that hump, part of it is about the mechanisms somewhat, and the last part is that they have to be willing to put in a little bit of time up front.

AJMC^®: How would you characterize the VICTORIA trial design and findings with respect to other recent trials in heart failure?

Ezekowitz: Most clinicians will probably look at their patients who are in hospital, or were recently in hospital within the last 6 or 12 months, and say, “That’s my group I’m going to target first because that’s what the trial really focused in on.” They’ll have a lot of ability to do so because of the broad renal function, broad ejection fraction, because those 2 big things really drive our practice rather than typical things like heart rate and blood pressure. I think it’s going to be that recently discharged patient that they focus on.

I do think that there’s lots of competition for getting medications on board in a patient, so patients may push back and say, “Hey, 1 at a time. I want to tolerate this one first.” That’s OK. There’s going to be some shared
decision-making around that, but these same patients have to realize that the window is open for a period of time, that we really need to work through that window quickly. We can’t say, “See you in a year, maybe we’ll think about it.” If somebody has cancer, we don’t say, “We’ll see you in a year when we may start another therapy.” We would never say that. We are going to be aggressive up front and start these medications to cure cancer. We would never think about saying things like, “Well, we’ve got 4 chemotherapy agents. A new fifth one came along, but we’re not going to add that in even though it can reduce your chance of a relapse.” That’s just not said in the cancer world. We have great therapies in the cardiovascular sphere that can change outcomes and lives, so why do we selectively not treat cardiovascular disease like we do with cancer?

AJMC^®: As you look to the future of clinical trials and research, what would you like to see emphasized, and what do you think is achievable when it comes to optimizing care for patients?

Ezekowitz: Different pathways and more targeted approaches are certainly desired and being explored. I think that’s going to be interesting, but it can take a lot longer to show and work in a targeted way; I think that one’s a little further away.

I do think that the way in which we manage people, the design of the system matters for the care around patients with heart failure or other acutely chronic diseases, such as COPD [chronic obstructive pulmonary disease] or renal failure. That system is where I think most of our action is going to be in getting the great therapies on board, following them up, being much more alert, so systems that do that well will actually succeed. It’s research into what is the best design for which patient, which is important.

I think that things, such as the wearables or digital health in the world of heart failure… They have not yet seen any of the major breakthroughs, with telehome monitoring not really showing any benefit in randomized controlled trials to the degree we expected. The difference is now we have much better fidelity of measurement, and I think patients are going to drive a little bit of this and say, “Hey, I want to be measuring my “X” factor, and if it shows I’m about to deteriorate, I’d like it to be intervened before I deteriorate, rather than after,” which is what we see in the ED. Digital health is going to help us understand that, but also, doing clinical trials in that area is going to probably lead to more gain than one would anticipate.

Maybe a third aspect of this is that we’re very focused on implantable devices, and I think that’s great and a contemporizing solution for LVADs [left ventricular assist devices] and other pacemakers. Those, I think, have seen their heyday, but I’m not certain they’re going to necessarily be the 1 thing that’ll actually win the game. We seem to have hit this kind of wall of development in that area where you just can’t change the other clinical outcomes as much as you would think for lower-risk patients. Device development has to change gears a lot to really get there.

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