DREAM-HF trial ‘legitimized’ cell therapy in HF
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In patients with HF, mesenchymal precursor cell therapy reduced risk for MI and stroke, especially in those with systemic inflammation, but did not meet the primary endpoint of improvement in recurrent nonfatal decompensated HF events.
Despite failing to meet the primary endpoint, data from the DREAM-HF trial revealed several hypothesis-generating insights into how cardiac cell therapy, injected into the heart muscle during a catheter-based procedure, might have significant benefit on the natural history of HF with reduced ejection fraction, according to Emerson C. Perin, MD, PhD, medical director at Texas Heart Institute.
In the intention-to-treat population of 565 patients, 28 of whom did not undergo a procedure due to protocol violations, the primary outcome of mean cumulative rate of recurrent nonfatal decompensated HF events per 100 patients did not differ between those assigned mesenchymal precursor cell therapy and those assigned the sham procedure at a mean follow-up of 29.9 months (HR = 1.2; 95% CI, 0.8-1.7; P = .406). However, the cell therapy group had lower rates of nonfatal MI or stroke compared with the sham group (4.6% vs. 13%; HR = 0.346; 95% CI, 0.18-0.664; P = .001), which was true regardless of whether patients had NYHA class II HF (5% vs. 14.2%; HR = 0.336; 95% CI, 0.122-0.923; P = .035) or NYHA class III HF (4.3% vs. 12.4%; HR = 0.351; 95% CI, 0.149-0.827; P = .017).
DREAM-HF is the largest clinical trial of cell therapy in patients with HFrEF to date.
Healio spoke with Perin about the link between inflammation and HF, the importance of nuance in trial design for new therapies, and how cell therapy can work in parallel with guideline-directed medical therapy in HF. The findings were first reported by Healio when presented at the American Heart Association Scientific Sessions in 2021 and have now been published in the Journal of the American College of Cardiology.
Healio: What role does inflammation play in HF, and how does it drive adverse events?
Perin: Immunity and inflammation are at the core of dysfunction in HF. The main players in maintaining HF, cellularly speaking, are proinflammatory macrophages. This smoldering fire that goes on, especially in ischemic patients, is characteristic in HF. Everything else we see in HF — edema, shortness of breath, congestion — are all neurohormonal maladaptive changes in HF. That constellation of findings is secondary to what the body is trying to do.
Healio: Inflammation is at the core of HF, yet therapies targeting inflammation have not been successful. Why is that?
Perin: There have been several trials in this area that were not successful. That is likely because these trials have targeted single inflammatory markers. That is not enough.
The beauty of cell therapy is, if you put the cell in an inflammatory environment — and we believe where you put the cell is very important — these cells have receptors for things like tumor necrosis factor (TNF) alpha, interleukin-6, interleukin-1 beta and more. These mesenchymal precursor cells, or MPCs, get activated through these cytokines in that inflammatory environment and in turn respond by polarizing M1 macrophages, the main things that keep HF going, into M2s, the pro-healing phenotype. The cells secrete stromal cell-derived factor 1, vascular endothelial growth factor and angiopoietin-1, while the M2s secrete interleukin-10 and platelet-derived growth factor. All of these are all pro-healing and anti-inflammatory. So, we have an amplification. The living cells we put in read the environment, signal things to different cells and transform the environment. What I find absolutely fascinating is this is done at a distance. We see improvement at the level of the cardiomyocyte, but we also see this dramatic decrease in MI and stroke. How? This is an anti-atherosclerotic therapy, in addition to being a HF therapy. These cells are immunomodulatory and anti-inflammatory.
Healio: This study missed its primary endpoints; however, there was a significant reduction in MI and stroke for people who received this therapy. Can you talk about the trial design for DREAM-HF? What were you and your colleagues looking for?
Perin: To frame this, I treated the very first patient with stem cell therapy in the world for the heart in Brazil in 2001. The first time an MPC was injected into a human for this therapy was 2007. Then we conducted a dose-finding trial, which gave us interesting signals. Now, we wanted to conduct a large phase 3 trial looking at clinical events.
There was one problem: We don’t know what we are looking for. People have trouble understanding that. In cell therapy, we do not know what the endpoints are, making trial design very tricky. Yet, we hold these trials for unknown therapies to these standard, orthodox trial parameters.
For DREAM-HF, the primary endpoint was recurrent hospitalizations. That is not what cell therapy does. This is not a decongestive therapy. Cell therapy works locally, and at a distance. Locally, we see an improvement in left ventricular ejection fraction across all patients that received the cells, which was statistically significant, and a dramatically significant reduction among the participants who had inflammation, defined as a C-reactive protein greater than 2 mg/L. We saw an amplified positive response in people with inflammation.
Then, we looked at a triple endpoint that included CV death. We had to prove that CV death contributed independently to the separation in the curves, and it did. We know that CV death contributed, and that is an important message. We have a therapy that decreases apoptosis. But it is also important to put the cells in the environment that has inflammation to see a local and systemic response.
If you look at all these big trials for other HF drugs, the endpoints group recurrent hospitalizations and cardiac death. Recurrent hospitalization is something that has to do with maladaptive changes in HF. CV death has to do with what is going on in HF and the events. We need to start thinking about therapies that address the cause and maintenance of HF, and then separately, all the guideline-directed medical therapy (GDMT) for HF. Everyone in DREAM-HF was receiving maximized GDMT. We saw an effect with MI and stroke that was unexpected; however, it all starts to make sense once you understand it. You realize that these cells are addressing a part of HF that was never addressed. These should be parallel efforts. Yes, we need to address the symptoms of HF, the decongestion, volume issues. But now we can address it at the molecular level also.
What is the take-home message from the DREAM-HF study for cardiologists?
Perin: As with any novel therapy, in cell therapy, there was a lot of hype in the beginning. We knew very little about it. Some patients responded, others did not. Then, you go back to the drawing board and have to figure out what is going on, how to apply it. We look at the administration, the dose, what cells to use, the timing of administration, which patients are ideal candidates. Do patients need repeat administrations of the therapy? Our to-do list is long.
The takeaway is we have turned the page on cell therapy. We are at a phase where, years later, with data, we are understanding what is happening. There are critics of this field. With this study, we have legitimized cell therapy in HF. I know this treatment works, I’m just not sure how to make it work. We have taken a major step in understanding how cell therapy can work in the heart and in HF. Cell therapy will open the door to a new way of treating HF that is complementary to what we do right now.
Healio: You mention your to-do list is long. What are the next steps for you and your team?
Perin: We need to do a confirmatory trial. I promise this: We will not get the endpoints wrong this time. We now have a blueprint for that, and we will have more data coming from DREAM-HF. I know what we need to do to get there, and we will get there. We look forward to making cell therapy an important part of treating HF.
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For more information:
Emerson C. Perin, MD, PhD, can be reached at eperin@texasheart.org.
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