Treatment for Heart Failure: Historical Overview

Transcript: Deepak L. Bhatt, MD, MPH: Let’s move on and discuss standard and novel treatments for heart failure. Javed, maybe you can provide us with a brief history of the various treatments for heart failure, maybe going back to ACE [angiotensin-converting enzyme] inhibitors, beta blockers, aldosterone antagonists, and ending with SGLT2 [sodium-glucose transporter protein 2] inhibitors?

Javed Butler, MD, MPH, MBA: Yes. This has been a phenomenal journey. Initially, the whole idea was to give vasodilators for hemodynamic improvement, so we started with hydralazine and nitrates. The primary issue was, how can we stabilize hemodynamics, improve cardiac output, and decrease their systemic vascular resistance? We were not necessarily thinking the way we think about outcomes now. Then came the question of, “Are ACE inhibitors better than vasodilators?” So we started comparing the 2. It turned out that, forget about vasodilation, patients given ACE inhibitors were actually feeling better and living longer. So that led to the whole era of the newer hormonal antagonists for heart failure.

We progressed from doing multiple studies in sick patients, less sick patients, post-MI [myocardial infarction] patients with ACE inhibitors and ARBs [angiotensin receptor blockers] and RAAS [renin-angiotensin-aldosterone system] inhibitors, which seemed like a really good idea. But then there were all these data with sympathetic nervous system activation, and heart failure outcomes were getting worse. Then beta blockers became an obvious choice. Obviously, when we say a RAAS system, it’s not only renin-angiotensin system. It’s renin-angiotensin-aldosterone system. So then we moved to the era of the beta blocker trials and aldosterone antagonist trials.

This was very much the same trajectory—look at mild to moderately sick patients, severely sick patients, post-MI patients. Then, no matter what you’re doing, you start seeing mortality benefits with all these things. There was some idea that the oxidative stress may be more important in African American patients who are a target of the study with hydralazine and nitrates. And again, we saw mortality benefits. Then let’s not forget about device therapy. Guided resynchronization therapy, defibrillator therapy in heart failure with reduced ejection fraction also was beneficial. So it’s sort of a 2-decade run of success across the board.

Now during this evolution, we were thinking that for all the bad things going on in the body, how can we make them better or make them good? Then came the investigators thinking about it in a little bit different way. I love the name of the trial—PARAGON-HF—that Dr Solomon and other colleagues came up with. This is really a paradigm shift in the way we think about heart failure. This was not only about attenuating the bad neurohormone, but actually accentuating the good neurohormone. So bringing a balance out. That led to the valsartan/sacubitril trial. You know, what an incredible success. So a lot of therapies, and life is getting a little bit complicated because we have too many successes.

Now we are moving into the next phase, where it’s not the traditional neurohormonal modulation but a completely different target. SGLT2 inhibitors are a, “Who knew?” These were diabetes drugs tested in cardiovascular outcomes trials. All of a sudden, heart failure was being prevented and those people with heart failure seemed to be doing pretty well. But the biggest thing is whether patients had diabetes or not, there was a hypothesis that they may benefit. So again, a shout out to Dr Solomon and his colleagues.

There’s also the DAPA-HF trial. I think the regulatory agency of the guidelines will be looking at the data pretty soon. But again, a complete mortality benefit. And no matter how you slice and dice, which subgroup you look at, clearly you’re seeing mortality and hospitalization benefit.

So we have come a long way. Another trial was recently presented at AHA [American Heart Association], so things are getting a bit complex—but complex in a good way.

Now, regarding heart failure with preserved ejection fraction, there has not necessarily been as much success. We have had a lot of trials that have been negative. But again, as mentioned earlier by my colleague, we don’t necessarily understand the pathophysiology as well as we do with reduced ejection fraction. We also don’t necessarily understand how the phenotyping works in that group.

But finally, we are almost there with PARADIGM-HF, with valsartan/sacubitril. We can also get a bit statistical here and say, “Well, what does 0.059 mean?” It almost reached statistical significance. But from a clinical perspective, there was a 15% risk reduction as well. So we are making strides in heart failure with preserved ejection fraction, but in regard to heart failure with reduced ejection fraction, that has been the trajectory over the past 2.5 decades.

Deepak L. Bhatt, MD, MPH: That was a really nice overview of a lot of data taken from multiple trials over decades. Scott, any thoughts there? Javed was really praising you and your work quite a bit.

Scott David Solomon, MD: Javed, thank you very much for that. I actually just want to make a point that a number of us will remember. When we were in medical school, or when I was in medical school, it was considered a contraindication to give beta blockers to patients with heart failure. That underscores the point that all those advances that Javed just talked about were due to these randomized trials done not just to find a new drug, but sometimes to discover that a drug we’d been using and thought shouldn’t be used was actually beneficial. I just wanted to make that point, Deepak, because we sometimes forget how important it is to do randomized clinical trials. We’re seeing that, of course, right now in the news every day.

Deepak L. Bhatt, MD, MPH: Absolutely. That is a great point. Nothing beats a good randomized clinical trial. George, before we get into different new drugs, like the SGLT2 inhibitors for heart failure, for example, maybe you can just briefly review...the rehospitalization rates for patients on these traditional heart failure medications?

George Bakris, MD: Nancy actually made a very good point earlier. In spite of all of these medicines, we really haven’t changed things that much. That’s been echoed by some of the other people. The study that I’m familiar with went out more than 10 years and looked at 3.2 million people. The incidence of heart failure basically increased from 91 to 1313 people. Huge increase in the people with diabetes—type 1 and type 2. So you’ve got incidence rates of heart failure hospitalization going from 2.4 to 12.4 per 1000-person years in this group.

Clearly, this has been a major problem, as somebody said, in terms of cost. But the morbidity is out of control. I want to make the point—because it was made by Nancy and by others—that if we’re not educating patients about the nuances of what they’re supposed to do, not just the general things, then how do you expect them to follow through? So I think it’s important to not just arm them with the right medicine and the right dose, but also to teach them how to use those along with lifestyle modification.

Transcript Edited for Clarity