With the deepening research on the pathophysiological mechanism of chronic heart failure, remarkable achievements have been made in recent years with new targeted therapeutic drugs. A breakthrough has also been made in the treatment of heart failure with ejection fraction retention (HFpEF). At ACC 2023, Professor Navin Rajagopalan from the University of Kentucky was invited to talk about the new treatment methods of HFpEF based on the latest research progress.
International Circulation: Chronic heart failure is a complex clinical syndrome in the advanced stage of cardiovascular disease and has become one of the major diseases endangering human health. Would you please introduce the new research progress on this topic at this conference?
Professor Navin Rajagopalan: As you say, chronic heart failure is becoming increasingly common in the United States and around the world. In the last several years, there has been the development of new medications to help with this disorder. A little over five years ago, a class of medications called angiotensin receptor-neprilysin inhibitors (ARNIs), a combination drug of sacubitril and valsartan, showed significant benefit in heart failure with reduced ejection fraction. And most recently, another drug class called the SGLT2 inhibitors have also shown benefits. Both of these classes on medicines were then studied in heart failure with preserved ejection fraction (HFpEF), which is also quite common, and unfortunately, historically, there has never been a drug that has shown benefit in that patient population. So first, sacubitril and valsartan were studied in that patient group, and then lately, SGLT2 inhibitors have been studied. Both have shown promise in heart failure with preserved ejection fraction, mainly in reducing heart failure hospitalizations. Unfortunately, both classes of medications did not show benefit in terms of survival. So whereas we have several medications that have shown survival in heart failure with reduced ejection fraction, we have not seen the same in heart failure with preserved ejection fraction.
Even though these medications have been around now for several years (and with the SGLT2 inhibitors coming along in the last couple of years), there is still the problem that many patients have not started on these medications. During ACC, we have seen that many investigators have catalogued this problem showing that those patients living in impoverished areas or those in socially disadvantaged areas of the country, unfortunately don’t receive the same care as those living in more affluent areas. Also, it is encouraging that many investigators have taken it upon themselves to see what they can do about this. There is a group in New York, for example. A lot of clinics now use electronic health records, so this group has looked at alerts that physicians would receive on the computer to encourage them to start medications. They found in their program that they were able to achieve significantly greater use of guideline-directed therapy of these new medication classes after a period of six months. I think anything that we can do as a community to widen the use of these medications in heart failure will lead to better outcomes.
In heart failure, we are always looking at newer technologies and newer devices. One of the technologies that a couple of years ago showed promise in heart failure was transcatheter edge-to-edge repair of the mitral valve. Historically, mitral valve disease, which is seen in heart failure, can only be treated with surgery. But the technology now exists where you can, in many cases, repair a leaking tricuspid valve with catheters so the patient does not have to have open heart surgery. A few years ago, there was a study called COAPT, which showed benefit of this technology in patients with heart failure and mitral regurgitation. They followed patients for two years. Earlier today at ACC, they showed that this benefit at two years was seen out to five years, so patients who had the repair of their mitral valve out to five years had better outcomes. Now the one caveat is that at five years, a lot of the patients who had received this repair were either still being admitted to hospital or unfortunately passed away. Less patients died who had received the therapy, but out to five years, outcomes were not ideal. This really highlights that we still have to do a much better job of trying to treat these patients and making sure they are on the appropriate therapies.
International Circulation: What is your opinion about the treatment of device implantation such as cardiac systolic regulator as a promising treatment for heart failure?
Professor Navin Rajagopalan: Cardiac contractility modulation (CCM) is a device that patients with heart failure have implanted. It is like a pacemaker, but it is different. Basically, it applies electrical signals to the heart during the absolute refractory period. This stimulates contractility to make the heart work better. There was a study published many years ago called FIX-HF, which, in a small group of patients, showed progress. Those of us in the heart failure field have patients who despite medication are still symptomatic, and this technology shows promise in that setting. At my institution, we do use this in a select group of patients. In the study, they did not show that people lived longer, but it did show that patients felt better - their quality of life was improved. The downside of the technology is that it is a device. It is the size of a pacemaker and needs to be implanted in the patient. It is not open heart surgery. Patients do not have to stay multiple days in the hospital to have the device implanted. This study was a smaller study and did not show that people live longer, but I think the promise of this technology may be in heart failure with preserved ejection fraction. As I said earlier, we don’t have a lot of therapies for this patient group. There is a trial called AIM HIGHer that is currently starting enrollment. Our institution is going to be a center for that study. We don’t have any data yet, but my hope is that a couple of years from now, we will show that in patients with heart failure with preserved ejection fraction, this therapy may have promise. That remains to be seen in the years to come.
International Circulation: In the guidelines, what are the recommended treatment options for HFpEF?
Professor Navin Rajagopalan: Currently in the guidelines, for heart failure with preserved ejection fraction, there are three classes of medication that have shown promise. One is mineralocorticoid receptor antagonists (MRAs), which is spironolactone. The second class id ARNI, which is sacubitril/valsartan (Entresto in the US). The last class is SGLT2 inhibitors - empagliflozin and dapagliflozin. All of them have mainly shown benefit in preventing hospitalization, which we know is very important for our patients, but the strength of evidence is not as great as what we see for those medicines for heart failure with reduced ejection fraction. So there is benefit, but unfortunately we are still struggling to find the one drug that we can tell the patient will help them live longer or that their heart failure will be reversed. Unfortunately, our therapies nowadays mainly treat symptoms and prevent hospitalization. They are in the guidelines. The newer guidelines will have SGLT2 inhibitors recommended for heart failure with preserved ejection fraction, but we are still waiting for the one drug that will make patients live longer with HFpEF.
International Circulation: What is your opinion about the application of new target drug and device therapy in HFpEF ?
Professor Navin Rajagopalan: For newer therapies, I mentioned cardiac contractility modulation (CCM) earlier and hopefully that can help. Earlier today, a group from Mayo published their trial called RAPID-HF, where patients with HFpEF may benefit from atrial pacing. Unfortunately, they did not see any benefit. It was a small study (30 patients in each arm), but unfortunately a negative study. It did not show any benefit. It was published also today in JAMA. So we are still looking for that one therapeutic device or medication that will show benefit in those patients.
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