Target Dose in HF Therapies for Reduced Ejection Fraction

James Januzzi, MD: We’ll get into the addition of other therapies in a second. Before we do that, the consensus document provides helpful practical information. It goes through the indications and the contraindications. What contraindications should clinicians keep in mind when they’re thinking about sacubitril/valsartan therapy?

Javed Butler, MD, MPH, MBA: Some of the obvious ones are if you have any allergic reaction with past exposure to these agents, that’s a contraindication, of all RAS [renin-angiotensin system] inhibitors, ACE [angiotensin-converting enzyme], ARBs [angiotensin receptor blockers] and now ARNI [angiotensin receptor-neprilysin inhibitor]. Because [sacubitril/valsartan] has an ARB in it, it’s not indicated in pregnant women because of the risk of fetal toxicity with a RAS modulation. Then there are some cautions, not necessarily contraindications per se, but caution because of the GFR [glomerular filtration rate] issue and in which patients it was studied. How do you use it if you have some degree of liver dysfunction or renal dysfunction? Then there are other cautions that are all common sense things: older people, lower blood pressure, etc. We can get into that a little. But first of all, in terms of the contraindication, because of the risk of angioedema, you don’t want to use it along with an ACE inhibitor. The reason it has valsartan in it and not enalapril is because of the risk of angioedema. If you have a history of angioedema, don’t use it. If you are on an ACE inhibitor, stop the ACE inhibitor for 36 hours before you start, so those drugs have washed out of your body. And again, a pregnancy, or a previous allergic reaction.

James Januzzi, MD: Yes, that’s very useful guidance. This is all in the document and helps to understand when and how to use a drug, but also when not to. How to use the drug is also important, because one of the things that I mentioned early on is this concept of target dose. This is once again a manifestation of the clinical trials and how the drugs were studied. The target dose is the dose that was studied in clinical studies, and we don’t know if higher or lower doses of any of the therapies we use are the biologically optimal dose. Regardless, we do focus heavily on this idea of target doses, and in the document, we provide a list of target doses not just for sacubitril/valsartan, but for all of the therapies we use in chronic heart failure with reduced ejection fraction. Javed, from a perspective of target dose achievement, let’s speak in a more general sense about all therapies that we give, and then we’ll circle back to sacubitril/valsartan. Philosophically, what are your thoughts about target dose and how to achieve it?

Javed Butler, MD, MPH, MBA: This goes back to the art of medicine a little. I was just having a talk with the residents the other day. I said, “If you have $100 and you’re hungry, thirsty, and your car doesn’t have gas, it doesn’t make sense to spend all the money on eating or drinking or filling up with gas. You’re better off doing a little of everything. But in an ideal world, it would be great to have all 3 of them be fulfilled.” It’s sort of the same example. My opinion on the dose issue is that we should absolutely strive to achieve target doses that were studied in the clinical trials. That’s what the evidence tells us. But, don’t do it up front with 1 drug and run out of your ability to take blood pressure, creatinine, potassium [medications], whatever will limit your use of the other therapies.

At this point, we have 5 pathways, modulation of which 4 drugs have been shown to improve outcomes, and it’s a better strategy to block all the pathways at some level first. Once you have blocked all the pathways at some level, then uptitrate the medication, but don’t uptitrate up front because it leads to 2 problems. If you uptitrate β-blockers or ACE inhibitors or ARNIs to the maximum doses, you might run out of blood pressure or creatinine or whatever the spending functions you have of these physiologic parameters, and you may not be able to use another medication. That’s 1 problem. And then the second problem is that you also delay the blocking of the other pathways. We know that going from a low dose to a high dose improves outcomes further, but we also know that the biggest bang for the buck is getting them to start the medication. My philosophy is to cover all pathways at low doses and then, as rapidly as you can, try to achieve the target dose.

James Januzzi, MD: Ladies and gentlemen, you heard it here today from Dr Javed Butler. If you read the document, that is exactly what the document says, and it is thanks largely to the influence of Dr Butler and the writing committee. That’s why the document says it, but it’s true. If you’ve got numerous pathways to block, and you only achieve blockade of 1, possibly with a dose much higher than needed to block that pathway, you’ve lost the opportunity to improve prognosis. The document goes through useful tips about how to titrate. And in the case of sacubitril/valsartan, one very important tip—and this also possibly goes for the next class of drugs we’re going to talk about, the SGLT2 [sodium-glucose cotransporter-2] inhibitors—is to begin modifying your loop diuretic dose to try to afford some blood pressure headroom.

Interestingly, especially with some of the newer therapies we give—angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists and SGLT2 inhibitors—because each has either a natriuretic or diuretic effect to some extent, it helps us to get away from the loop diuretics. The reason that’s important is because loop diuretics, although they improve symptoms and no doubt reduce hospitalizations, they have no beneficial effect on mortality at best. At worst, they may actually increase mortality, especially at higher doses. These drugs exert benefit not just because of their biological effects, but because of their facilitation of avoidance of therapies that might increase risk, such as loop diuretics. Titration is an art and a science, and the document really focuses on this.

Transcript Edited for Clarity