How Many Drugs Does a Heart Failure Patient Need? (09/2004)

DOLPH HUTTER, MD: Hello, I'm Dolph Hutter. Welcome to the American College of Cardiology Conversations with Experts. In this program, we will examine the question, "How Many Drugs Does a Heart Failure Patient Need?"

Joining me to discuss this is Michael Givertz, Assistant Professor of Medicine at Harvard Medical School at the Brigham and Women's Hospital. And via telephone, I'd like to welcome Dr. James Udelson, Associate Professor of Medicine at the Tufts New England Medical Center, and Dr. Bertram Pitt, Professor of Medicine at the University of Michigan Health System. Thank you all for joining me.

MICHAEL M. GIVERTZ, MD: Thanks for having me.

DOLPH HUTTER, MD: Let's start out, and Bert I'm going to ask you to start out here. We've got the heart failure patient, and he definitely has heart failure. What are the basic drugs that we should have on board literally in all people with systolic heart failure?

BERTRAM PITT, MD: Well, I think if we're talking about systolic heart failure, with an ejection fraction, let's say, somewhere less than 40%, and clinical signs of heart failure with some fluid overload, then I think most of us would agree that the patient is probably going to be on a loop diuretic, an ACE inhibitor and a beta-blocker.

I think that would be the base of therapy. And then, depending upon how the patient reacted, how severe he was, there are several other options that one would consider, adding things like our old friend digoxin, an angiotensin receptor blocker, or probably an aldosterone blocker.

DOLPH HUTTER, MD: Okay, good. And we're going to come back to those things. Now, Jim, let's see. With the beta-blockers and the ACE, let's first of all talk about the beta-blockers. And, by the way, everybody feel free to comment any time. What beta-blockers should we use? Is there one or is it the other? What's the data on that?

JAMES UDELSON, MD: Well, at this point, most of the evidence involves carvedilol, or Coreg, or long-acting metoprolol, or Toprol-XL.

Other drugs have been studied in other countries, but I think for the most part in the United States, most people would use one of two, because that's where most of the evidence comes from. At this point, there's not as much evidence for short-acting metoprolol, and so for the most part those are the two drugs that should be used.

DOLPH HUTTER, MD: Okay. Do you have a preference? And if so, why?

JAMES UDELSON, MD: Well, it depends. I think the way I usually practice is that for people on the more advanced end of the spectrum, the more severe heart failure patients, I tend to use carvedilol. There's more data from the COPERNICUS trial, for instance, in the more severe patients. You know, perhaps there it's a little bit easier to uptitrate. And for the people on the other end of the spectrum, younger people with minimally symptomatic cardiomyopathy I would tend to use Toprol-XL because it's once a day.

DOLPH HUTTER, MD: Okay. Mike, what's your feeling about the beta-blockers?

MICHAEL M. GIVERTZ, MD: I'd agree with some of the comments that Dr. Udelson has made. I think that carvedilol is often my first choice of beta-blocker. I also would consider carvedilol, perhaps, in patients who have a little bit more blood pressure to work with, patients with diabetes in whom there may be some other metabolic effects of carvedilol. This is based on some smaller trials.

If compliance is an issue, I think once-a-day Toprol-XL may be the preferred agent.

DOLPH HUTTER, MD: Good point.

MICHAEL M. GIVERTZ, MD: In addition, if a patient has reactive airways disease, I might err on the side of a beta-1-selective drug, like Toprol-XL.

DOLPH HUTTER, MD: Yes, yes. We should comment about the airway disease, because there was a recent review of this pointing out that the vasodilatory effect of carvedilol may actually protect the lungs a little bit so that they would argue, "Go ahead and try it in those patients, too."

I might point out there are additional actions of carvedilol compared to metoprolol. Is that correct? They have more of an independent vasodilating activity and a little stronger antioxidant activity. Do you think those are significant? Mike, why don't you answer, then Bert, I'd like to get your opinion.

MICHAEL M. GIVERTZ, MD: Well, there is some evidence that the alpha-blocking effects of carvedilol may be less important over time in patients on chronic carvedilol therapy. I think the argument that the antioxidant benefit of carvedilol makes it a preferable agent is really based on some smaller studies, some laboratory evidence. And I think in clinical practice, at least some studies that have looked at the antioxidant effects of beta-blocker therapy, have not clearly shown a difference between the agents.

DOLPH HUTTER, MD: Okay. Bert, what's your reading about those two agents?

BERTRAM PITT, MD: Well, I think I would agree generally with what's been said, and I'd just like to emphasize that probably short-acting metoprolol, which is still used quite widely, is not as good as either the long-acting metoprolol or the carvedilol.

DOLPH HUTTER, MD: Okay. Very good point that two of you have made so far. Right. All right.

Now, I might just throw out, there are also a lot of people don't understand that a nonselective beta-blocker will slow the heart rate more per drop in blood pressure than a more selective beta-blocker. So if I have somebody with kind of a fast heart rate, that leans me more toward a carvedilol, also, rather than metoprolol, which is not quite as effective on the heart rate.

Jim, what about the ACE inhibitors? Do you start a beta-blocker first, and then an ACE inhibitor, or do you start them both at the same time? And then what ACE inhibitor would you use?

JAMES UDELSON, MD: Well, I think in terms of the timing, I think at this point most people would start the ACE inhibitor first, followed by a beta-blocker, only because that's been the clinical experience with the beta-blocker trials, starting them in people who are already on ACE inhibitors.

DOLPH HUTTER, MD: Excellent point. Excellent point.

JAMES UDELSON, MD: And the main issue is how far to up-titrate, and do you maximize the ACE inhibitor and then try and get a beta-blocker on board? And I think the short answer to a complicated question is, it's probably preferable to be on moderate doses of both than a very high dose of one and not be able to get the patient on the other.

DOLPH HUTTER, MD: Good point. And would you also agree, if you have room to move, pushing up to a higher dose of an ACE inhibitor, if you can, gives you more efficacy?

JAMES UDELSON, MD: Well, we don't exactly know that, but I think it's very good practice to say that clinicians should aim for the target dose of the drugs that was used in the large clinical trials.

And in terms of your point about which ACE inhibitor, at least, I would think at this point there's been a lot of evidence with a lot of them, and I think most people would consider it a class effect in terms of heart failure, although differences can be identified physiologically, and I would tend over time to choose the simplest, once-a-day, least expensive, based on the patient's health plan.

DOLPH HUTTER, MD: Bert, do you agree with that? In terms of heart failure, now. I'm not preventing subsequent events in coronary artery disease. Do you think it's a class effect with the ACE inhibitors?

BERTRAM PITT, MD: Well, I hate to say class effect, because I don't think the FDA recognizes that, and I'm not so sure that it's absolutely true. But it also is probably true that so far most of them have worked. But the question is, what dose do they work at?

DOLPH HUTTER, MD: Yes.

BERTRAM PITT, MD: So I'd like to pick the ones that have been studied so I know the target doses. Even though they probably all would work, I don't want to spend my time trying to figure out what dose.

DOLPH HUTTER, MD: Okay. Mike, what's your take on this, the ACE inhibitors?

MICHAEL M. GIVERTZ, MD: I would agree with Bert's comments. I think if I'm going to use a drug like captopril, certainly I would shoot for the target doses that were used in the original trials. More typically, I'm using a once-a-day ACE inhibitor like lisinopril, trying to get up to doses of 20 or even 40 mg once a day.

DOLPH HUTTER, MD: Okay. Yes. Go ahead. Who was that? Bert?

JAMES UDELSON, MD: No, this is, this is Jim.

DOLPH HUTTER, MD: Or Jim, yes.

JAMES UDELSON, MD: I think the point that everyone is making about the target dosing is really important.

DOLPH HUTTER, MD: Yes.

JAMES UDELSON, MD: I think if you look at surveys, patients are very underdosed with all of these therapies in heart failure, and trying to achieve the target doses is really very important for patients.

DOLPH HUTTER, MD: Yes, and I think, as you pointed out, that starting the ACE inhibitor first, I mean, you can get there pretty fast. You can titrate fast, whereas with carvedilol or metoprolol you have to start slow and kind of gradually build up over time.

Now, what about the role of diuretics here? Would you start them right away? Would you want to get them dry before you start an ACE inhibitor? Mike, how do you throw diuretics into this mix?

DOLPH HUTTER, MD: Bert, by the way, said loop diuretics, and so you might comment specifically.

MICHAEL M. GIVERTZ, MD: I think oftentimes we meet patients during an initial hospitalization for heart failure, and these medicines often get started either concurrently or one after the other. Most heart failure hospitalizations are associated with fluid overload, requiring diuretic therapy. I think loop diuretics usually are the first agents of choice, and I would agree with that. I think, in general, these medicines are being used concurrently, particularly in the symptomatic patient.

And I'd be curious with both Jim and Bert what their comments would be in terms of what…

DOLPH HUTTER, MD: We're going to get those next.

MICHAEL M. GIVERTZ, MD: …once you achieve euvolemia in a stable patient that you're following, say, in your office, is there a role for actually backing off on diuretic therapy?

DOLPH HUTTER, MD: Yes, okay. Bert, would you start the diuretics, get them dry initially and then start these other things?

BERTRAM PITT, MD: Well, I usually start an ACE inhibitor and a diuretic, but I like to get them fairly dry before I start a beta-blocker.

DOLPH HUTTER, MD: Excellent point. An excellent sequence, yes.

BERTRAM PITT, MD: And, and then I think we make a mistake, often, once we get them dry, keeping them on that same dose.

DOLPH HUTTER, MD: Yes.

BERTRAM PITT, MD: I think at that point when they become less symptomatic and are ready to be as an outpatient or in the maintenance phase, I think we should drop back to the minimal effective dose.

DOLPH HUTTER, MD: Okay, good. As far as the diuretics are concerned?

BERTRAM PITT, MD: Yes.

DOLPH HUTTER, MD: Right. And Jim, do you buy into that philosophy?

JAMES UDELSON, MD: Absolutely.

DOLPH HUTTER, MD: Okay.

JAMES UDELSON, MD: I think there was a little-known study years ago where, after patients were initiated on ACE inhibitors, a third of them could be taken off diuretics and maintain a good symptomatic stake.

DOLPH HUTTER, MD: All right.

JAMES UDELSON, MD: So that's a very under appreciated fact.

DOLPH HUTTER, MD: Good, good points now. So you're going to get them dry, but this is symptomatic therapy, and it's heart function therapy. And once you get the good volume status, they have no prophylactic value in themselves, whereas the beta-blockers and the ACE inhibitors do.

By the way, I just want to throw in a plea for all of us, you know, listening and talking about this thing. Remember to look at the neck veins. The jugular venous pressure really tells you about the volume status, much more so than anything else. And I just record them in centimeters of blood, you know. 5 cm with the angle of Louis as a reference point, and that's extremely helpful. Weight can be a little bit more problematic.

Okay, so we got the ACE inhibitor. Now, Bert, what about ARBs? Should we ever use ARBs before ACE inhibitors? And then a second question is, if not, should we ever add ARBs to an ACE inhibitor? Bert, what's your take on that?

BERTRAM PITT, MD: Well, as far as before, I think the bulk of the evidence is with ACE inhibitors, and so far, at least in chronic heart failure, when we did the comparative studies in ELITE, the ACE inhibitors came out a little bit favorable, more favorable than the ARBs, though in post-infraction they seemed to be equal.

But I think most people would sort of recommend an ACE inhibitor, and the only time we would start with an ARB is when the patient has clearly shown intolerance to the ACE inhibitor.

DOLPH HUTTER, MD: To an ACE inhibitor, right. Jim, do you agree with that?

JAMES UDELSON, MD: Absolutely.

DOLPH HUTTER, MD: Okay.

JAMES UDELSON, MD: And I think at this point I would immediately go to an ARB if the patient had a cough side effect from ACE inhibitors.

DOLPH HUTTER, MD: Right, yes, yes. My own experience with the cough is that it almost never goes away. You can fiddle with it, but that's one big indicator for an ARB, and obviously allergic reactions.

Mike, how do you handle that? Do you agree with this philosophy so far?

MICHAEL M. GIVERTZ, MD: I think for the patient who's truly intolerant to an ACE inhibitor due to cough, I think we'd all be comfortable switching them to an angiotensin receptor blocker. I think the more difficult situation is in a patient who is intolerant due to what some have defined as a cardio or renal limitation: hypotension, hyperkalemia, worsening renal function.

DOLPH HUTTER, MD: Yes.

MICHAEL M. GIVERTZ, MD: I think one would expect that the adverse effect may be similar with an angiotensin receptor blocker, although that's not always the case. And we should also recognize, as we have in our own population, that despite the fact that we used to think that most patients, if we tried hard enough, we could get them on an ACE inhibitor. There really are a significant minority of patients, maybe as high as 25% of patients, with advanced heart failure, who truly are intolerant to an ACE inhibitor, and that's at very least a marker of serious disease.

DOLPH HUTTER, MD: And, you know, you make a very good point about, you know, hypotension. They're not tolerating, and that, again, is that if the jugular venous pressure is too low they might need to run a little higher volume status in order to keep the blood pressure up and the renal perfusion up so that you can get these drugs on board. So we don't want these people necessarily too dry, do we?

MICHAEL M. GIVERTZ, MD: I think that's a reasonable point, although I think we often err on the other side.

DOLPH HUTTER, MD: Yes.

MICHAEL M. GIVERTZ, MD: Whereas we have a lot of patients who are probably walking around with unrecognized hypervolemia.

DOLPH HUTTER, MD: Okay. Again, I'm going to plead for that neck vein examination and...

MICHAEL M. GIVERTZ, MD: Very good. Very good.

DOLPH HUTTER, MD: ...teach everybody how to look at it. Bert, do you ever add an ARB to an ACE inhibitor?

BERTRAM PITT, MD: Well, I think the answer is yes, but I may differ with some of the others here just because I think the evidence with adding an ARB is sort of mixed.

On the one hand, we have the results from Val-HeFT, which show us on top of an ACE and a beta-blocker there's no benefit on mortality.

On the other hand, we have CHARM with candesartan showing us there is.

DOLPH HUTTER, MD: Yes.

BERTRAM PITT, MD: And I think I need some more data to tell me what's the truth.

DOLPH HUTTER, MD: Well, actually, didn't Val(sartan) have to show a negative effect when you added…

BERTRAM PITT, MD: A negative effect on mortality.

DOLPH HUTTER, MD: If you add it to an ACE inhibitor and...

BERTRAM PITT, MD: ACE inhibitor, beta-blocker. Right.

DOLPH HUTTER, MD: ...and beta-blocker. Yes. I wanted to get that point out. Yes.

BERTRAM PITT, MD: Whereas CHARM showed a beneficial effect.

DOLPH HUTTER, MD: Right, yes. So that's kind of a mixed marriage, or mixed benefit, I guess.

BERTRAM PITT, MD: Yes.

DOLPH HUTTER, MD: Basically, are you kind of reluctant to add it to, or how do you…

BERTRAM PITT, MD: Well, I think my first choice in severe heart failure, and this reflects my bias, I guess, is to add an aldosterone something like spironolactone.

DOLPH HUTTER, MD: Before mixing it, yes.

BERTRAM PITT, MD: Before adding an ARB. But I think there are other people that would add an ARB first, and I think there's no direct comparative trials.

DOLPH HUTTER, MD: Jim, how do you handle that? Do you ever combine them?

JAMES UDELSON, MD: Well, rarely. I think there might be one instance in the patient who doesn't tolerate a beta-blocker at all where the evidence from those trials might suggest that adding an ARB to an ACE inhibitor when the patient is not on a beta-blocker may indeed be helpful.

DOLPH HUTTER, MD: Good point. Good point. Mike, do you combine them very frequently?

MICHAEL M. GIVERTZ, MD: Well, I think my practice has evolved a bit. I think when VALHEFT was published, I think I had some patients who were on triple therapy, and I actually ended up taking them off of the ARB.

DOLPH HUTTER, MD: Triple therapy? Now, an ACE inhibitor...

MICHAEL M. GIVERTZ, MD: ACE inhibitor and an ARB.

DOLPH HUTTER, MD: ...beta-blocker and an ARB. Right.

MICHAEL M. GIVERTZ, MD:

I think data from both CHARM and the VALIANT post-MI trial at least has made me more comfortable with that combination that I think there's probably not adverse risk.

But I would agree, actually, with Dr. Pitt in that, you know, although you can take the evidence from CHARM and VALIANT suggesting that there may be a benefit, particularly from CHARM, in the addition of an ARB, a very small percentage of those patients were actually on an aldosterone receptor antagonist. So my preference also in patients with more moderately severe or advanced heart failure would be to start with spironolactone before adding an ARB.

DOLPH HUTTER, MD: Let's move into that know, and I'm going to ask you about the spironolactone and eplerenone, and then I'm going to come back, we have just a few minutes left, about when do we start? How sick does the patient have to be?

So, first of all, what about spironolactone? When do you use it? What are the comparisons between spironolactone and eplerenone? Bert, you've done some work on this. Can you start it off?

BERTRAM PITT, MD: Well, first of all, let me say they're both good blockers of the mineral corticoid receptor, and there haven't been direct, good direct, comparative trials.

So in chronic heart failure from the RALES trial, the experiences with spironolactone in postinfarct heart failure, it's with eplerenone. But I think they're both good.

The real difference is in their side effect profile in that spironolactone has sexually related side effects, because it downregulates androgen receptors and upregulates progesterone receptors, whereas eplerenone just doesn't have the same degree of side effects.

DOLPH HUTTER, MD: How about the effect on potassium? Is that comparable?

BERTRAM PITT, MD: It probably is comparable. There may be some less hyperkalemia with eplerenone. That's more theoretical than proven.

DOLPH HUTTER, MD: Is there a big cost difference?

BERTRAM PITT, MD: There's a big cost difference. Spironolactone is generic. It's been around for 40 years. And, it depends where you are, it's pennies, whereas eplerenone is priced identically just about to carvedilol. It's about a dollar and a half or more than that a day.

DOLPH HUTTER, MD: Wow. Yes. A big difference, yes.

BERTRAM PITT, MD: It's 3, maybe $3. It's quite a bit. I don't know what it is.

DOLPH HUTTER, MD: So you could make an argument, in terms of cost effectiveness, spironolactone is pretty hard to beat so far.

BERTRAM PITT, MD: From cost effectiveness. But you've got to be careful with those words, because of the fact, what's cost effective is what the patient stays on the longest.

DOLPH HUTTER, MD: Excellent point.

BERTRAM PITT, MD: And if they don't tolerate something and they drop off and tip over to manifest heart failure that's not very cost effective.

DOLPH HUTTER, MD: And of course, gynecomastia can be a real nuisance for some patients, too.

BERTRAM PITT, MD: Absolutely. Yes.

DOLPH HUTTER, MD: Now, Jim, what's your read on this, of the two agents? And also, when do you throw this on board as the third agent?

JAMES UDELSON, MD: I would agree with everything Bert said about the comparison, and generally in advanced heart failure patients, the type of patient that was studied in RALES with advanced symptoms or class III symptoms with a recent hospitalization, that's the target population for spironolactone in that trial, and that's now routinely added.

DOLPH HUTTER, MD: Okay.

JAMES UDELSON, MD: It's, you know, the data are very impressive. And the post-MI patient with LV dysfunction, as was studied in the EPHESUS trial, again, significant mortality benefit. That's the target for that drug.

DOLPH HUTTER, MD: Okay. Mike, your thoughts are pretty much the same?

MICHAEL M. GIVERTZ, MD: I think the one sort of patient population we're still a little bit up in the air about are the patients with mild or mild to moderate symptomatic left ventricular dysfunction. I think another important point which I'm sure we would all agree with is once you do make the decision to start an aldosterone receptor blocker, it's extremely important, obviously, to monitor closely for any changes in renal function or serum potassium levels.

DOLPH HUTTER, MD: And potassium, right. Yes.

MICHAEL M. GIVERTZ, MD: And I think even the more recent studies looking at real-world use of these agents in patients across the spectrum of heart failure has shown perhaps higher rates of both hyperkalemia and adverse events related to hyperkalemia that were seen in, obviously, the FOCUS clinical trial.

DOLPH HUTTER, MD: And speaking of hyperkalemia, just a couple quick points for our listeners. Remember, you can switch a little of the Lasix to hydrochlorothiazide, which is a very kaluretic diuretic. Don't forget to tell them to stop their potassium supplementation, et cetera, et cetera, before you back off on these drugs.

We only have a couple minutes left.

BERTRAM PITT, MD: A comment?

DOLPH HUTTER, MD: Absolutely. Absolutely.

BERTRAM PITT, MD: I think it's important when you talk about aldosterone blockade to remember that in both RALES and EPHESUS we excluded people with baseline renal dysfunction, and certainly with a potassium of 5 or above. And probably the smart thing to do is to calculate creatinine clearance by Cockroft-Gault or something else.

DOLPH HUTTER, MD: Okay.

BERTRAM PITT, MD: And exclude people with a creatinine clearance, certainly, less than 30.

DOLPH HUTTER, MD: Great, great, great point. Those are superb points. What about digitalis? Mike, what about digitalis? Any role?

MICHAEL M. GIVERTZ, MD: Sure. I still use digoxin in many patients with -- who remain symptomatic on all of the therapies we're discussed. With more advanced heart failure, I think it's still a reasonable drug for treatment of symptoms. It's been shown obviously to improve exercise tolerance and quality of life and…

DOLPH HUTTER, MD: And decreased hospitalizations, too, right?

MICHAEL M. GIVERTZ, MD: And decreased heart failure hospitalizations. I think the most important point I would hope that we'd all agree with is, we now tend to run both the doses and the serum digoxin concentrations lower than we used to.

DOLPH HUTTER, MD: What level? About 1.0?

MICHAEL M. GIVERTZ, MD: Well, certainly I'd like to see the level less than 1, and perhaps even in the 0.5 to 0.8 range.

DOLPH HUTTER, MD: Really? Okay. Jim, Isordil and hydralazine, and we're going to move right on to, do we still use those drugs?

JAMES UDELSON, MD: Well, at this point I think if patients do not tolerate ACE inhibitors or ARBs, that would certainly be quite reasonable, and I think most people have heard the news releases about the A-HeFT trial, African-American Heart Failure Trial, that will be presented at the American Heart Association meeting suggesting a mortality benefit in that population. And if that's true, when that is presented, we may then have to reevaluate that combination in the contemporary era for everybody.

DOLPH HUTTER, MD: Yes, that's right. And maybe African Americans respond better to that combination than non-African Americans. Bert, do you use the combination Isordil and hydralazine in addition to beta-blockers and ACE inhibitors?

BERTRAM PITT, MD: Well, just like we were talking about for digoxin, when people remained symptomatic, for years we've added Isordil and hydralazine on top of an ACE and a beta-blocker to get symptom relief.

DOLPH HUTTER, MD: Yes.

BERTRAM PITT, MD: In the new data, they suggest, is mortality benefits, so we'll have to wait for that.

DOLPH HUTTER, MD: Yes.

BERTRAM PITT, MD: But certainly, blood pressure is a consideration. But if they can tolerate it, it often reduces peripheral resistance and improves forward output and improves exercise tolerance.

DOLPH HUTTER, MD: And of course, you don't have to use both. I mean, you can use nitrates alone if you're just trying to decrease the venous return of the right heart and for pure symptom relief.

BERTRAM PITT, MD: Well, if you use nitrates alone, Dolph...

DOLPH HUTTER, MD: You're going to get tolerance?

BERTRAM PITT, MD: ...see if you can get tolerance to it.

DOLPH HUTTER, MD: Yes, yes.

BERTRAM PITT, MD: And hydralazine prevents some of the tolerance.

DOLPH HUTTER, MD: Excellent point. Very well taken. Yes, okay.

So I guess in summary, then, we all want our patients on beta-blockers and ACE inhibitors, and then we kind of go from there. ARBs if they can't take ACE inhibitors. Low threshold to adding either spironolactone or eplerenone to the patient. And for symptoms, the possible use of a combination of nitrates and hydralazine. And Bert just reminded us, the combination's better than one alone because of the tolerance situation. And a volume status that ought to be ideal for that patient consistent with good perfusion and yet an adequate blood pressure.

MICHAEL M. GIVERTZ, MD: And checking the neck veins.

DOLPH HUTTER, MD: And checking the neck veins, right. Okay. Listen, guys. Thank you very much. That's just been a superb discussion. A complicated area and a lot to get out there, and you guys did a great job. And thank you all for listening to us. I'm Dolph Hutter.