Blocking the RAAS Pathway in Heart Failure

Sheryl Chow, PharmD, BCPS; Akshay Desai, MD; Peter L. Salgo, MD; Scott Solomon, MD; and Orly Vardeny, PharmD, MS, provide an overview of the historic approach to blocking the renin-angiotensin aldosterone system in heart failure management.

Peter L. Salgo, MD: Let’s discuss RAAS (renin angiotensin aldosterone system) and angiotensin-converting enzyme (ACE) inhibitors. Where are we with all of this, Orly? How does this all fit together in the big puzzle?

Orly Vardeny, PharmD, MS: ACE inhibitors were the first RAAS blockers that were being used in the setting of heart failure with reduced ejection fraction. This is thought to be a class effect, but not the only way to block the RAAS system. So, thereafter, angiotensin receptor blockers (or ARBs) came about secondarily after ACE inhibitors were already on the market. Now, the guidelines focus on use of the ACE inhibitors, preferentially, and the use of ARBs if a patient does not tolerate an ACE inhibitor. Both can be used, but ACE inhibitors are preferred.

Peter L. Salgo, MD: Then we have MRAs (the mineralocorticoid receptor antagonists). Where do they fit in? How does this all work?

Sheryl Chow, PharmD, BCPS: It’s interesting because you use MRAs as additive therapy, but both the ACE inhibitor or ARB and the MRAs target the same RAAS system. You may ask, why am I using both when we’re targeting one pathway?

Peter L. Salgo, MD: I was going to ask that. Why are we using both?

Sheryl Chow, PharmD, BCPS: I guess the thought is similar to some data that showed that even if you block the pathway with an ACE inhibitor or an ARB, there’s still something called “aldosterone escape,” and, therefore, it needs to be inhibited on 2 levels: 1 with an ACE inhibitor or an ARB and the other with an MRA, if at all possible.

Peter L. Salgo, MD: And then there are the specific aldosterone antagonists. Let’s throw that in the pot and stir. How you decide how to make this cocktail work? Is there a stepwise approach to it? What do you do?

Orly Vardeny, PharmD, MS: It’s not an exact science. There’s an art to it. We know that we want our patients to be on all 3. We want them to be on a beta-blocker, we want them to be on a blocker or RAAS, an ACE inhibitor, an ARB, and we want them to be on spironolactone or eplerenone. But we can’t add all of these at the same time, so we’ll start with an ACE inhibitor at low dose and we’ll add a beta blocker at a low dose. Guidelines tell us that we can go back-and-forth, first titrating the dose of an ACE inhibitor and then titrating the dose of a beta blocker until we’ve reached target doses that have been proven to be beneficial in clinical trials. And then, somewhere along the way, we can add spironolactone. Others may add an ACE inhibitor first and then stay with a low dose, add a beta-blocker, titrate it all the way up to target doses that are proven to be effective, and then titrate the dose of an ACE inhibitor up if there’s blood pressure room left to play with.

Peter L. Salgo, MD: I work in an intensive care unit. All of this sounds complicated. You’re dealing with patients with low ejection fractions, many of whom are sick. Do you do this as an outpatient procedure or do you do this to hospitalized patients?

Scott Solomon, MD: You do it to both. In the hospital, you have the advantage of having very close control of these patients. You’re watching their blood pressures. If you’re worried about hypotension, you at least have them under scrutiny. You’re checking their pressures every few hours, usually. You can make sure they’re euvolemic because one of the biggest problems when you give any of these drugs is if you dry patients out too much (which we tend to do when we’re treating heart failure patients). Then you give them a RAAS inhibitor and you can get into trouble with hypotension. You can control all of that in the hospital fairly well. As outpatients, you have a little bit less control, but we still have to do it.

Akshay Desai, MD: I think this is one of the reasons that heart failure has become the paradigmatic example of collaborative care, because we have physicians working with nurses and pharmacists to titrate this regimen over time in an efficient way, with careful surveillance [by] laboratories. A patient’s potassium doesn’t get too high and their kidney function doesn’t get worse. It’s hard work, but if you are seeing patients on a frequent basis and making small incremental changes in pursuit of the goals that Orly outlined, then you can get there. And that’s what we need to do.

Peter L. Salgo, MD: You make this disease sound dangerous. You make it sound as if you’re not careful, people can get into trouble. And yet, you’re telling me, if you’re careful, you can start initiating therapy as an outpatient. If you bring them back enough, I hear you saying you can continue to upramp this stuff and get them optimized. Is that fair or do you just bring them all in and treat them for a week and send them home?

Akshay Desai, MD: Well, you can’t get all the medicines up that quickly.

Sheryl Chow, PharmD, BCPS: It takes time.

Akshay Desai, MD: But I do think it does help, and the data would support this—to start things. If you have a new diagnosis in the hospital, it helps to get the train started a little bit by starting a little bit of each of the medicines before they leave and then letting people uptitrate in the outpatient setting.

Orly Vardeny, PharmD, MS: The hospital is good. It’s an opportunity because the patient is there and there is a captive audience. It’s an opportunity to see what things they may be taking, if they’re on the right doses, and to consider, maybe, what things can be added to the regimen for optimizing care.

Peter L. Salgo, MD: I’m a third-party payer, and I get a phone call from a doctor: “Hi, I’m going to bring this patient in for a week. He’s not all that bad, but I just want to sort of get his medications going. Will you pay for this?” What kind of an answer am I going to get?

Orly Vardeny, PharmD, MS: Probably not a positive one.

Peter L. Salgo, MD: Who’s going to pay for it?

Orly Vardeny, PharmD, MS: Well, the opportunity comes when the patient is in acute heart failure for another reason and they’re already in the hospital being managed for congestion. The oral diuretic hasn’t worked. We have to use something, intravenously, because they’ve got congestion. They can’t absorb their oral diuretic. So, while we’re diuresing or while we’re removing the excess fluid, there’s an opportunity to potentially start a new medicine or to optimize the dose of a different medicine.

Peter L. Salgo, MD: One of the things you said that scared me is that if they are euvolemic or slightly hypovolemic (which is where most people run when they’re being aggressively treated as outpatients) and then you start this stuff, you can run into big trouble and make them hypotensive. So, what I hear you saying, unless I’m wrong, is that you’re going to start giving fluid back to people with heart failure as you work this stuff in? Did I hear that incorrectly?

Scott Solomon, MD: Yes, you heard that incorrectly.

Peter L. Salgo, MD: Thank you.

Scott Solomon, MD: We’re not going to give fluid back, but you have to pay attention to how much diuretic you’re using.

Peter L. Salgo, MD: Oh, so you stop taking off as much?

Scott Solomon, MD: You might. It really depends on where they are and what their blood pressure is doing. You have to pay attention, obviously, to the blood pressure. We haven’t talked about heart rate, but that’s another thing that we’re going to have to, at some point, discuss because you want to look at both of these things. But this is the art that Orly was talking about: we are trying to manage a lot of balls in the air when we’re talking about the pharmacologic treatment of heart failure with reduced ejection fraction.

Peter L. Salgo, MD: Well, there are guidelines, right?

Sheryl Chow, PharmD, BCPS: There are. Before you move on, actually, Peter, I wanted to also address that there is a difference between “target dose” and “optimal dose.” Target is based upon the goal, what we’d like our patients to be, based upon clinical evidence (clinical trials). Optimized is based upon the patient’s own condition. So, you may not even be able to achieve target doses, yet the patient is optimized if the blood pressure is low (a systolic blood pressure of 100 mm Hg) and you can’t titrate up. At that point, the patient is optimized at that moment.