Heart Failure with Reduced Ejection Fraction
Treatment and Management: The Latest HFrEF Updates
Dapaglifozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, used for the management of type II diabetes mellitus. It improves glycemic control by inhibition of glucose reabsorption in proximal renal tubules, causing glycosuria. Given that SGLT2 inhibition in patients with type II DM reduces their risk of first hospitalization for heart failure, more data are needed to determine the inhibitory effects in patients with known heart failure with reduced ejection fraction (HFrEF), regardless of diabetes comorbidity.
McMurray et al (N Engl J Med 2019; 381) conducted a randomized, phase III placebo-controlled trial in NYHA class II, III, and IV patients with heart failure (HF) with ejection fraction (EF) of 40% or less, randomizing to receive 10mg daily dapaglifozin or placebo, plus recommended therapy. Endpoints of this study were a composite measure of worsening HF (urgent visit or hospitalization for IV therapy for HF ) or cardiovascular death.
The researchers concluded that among this patient population, risk of worsening HF or cardiovascular death was lower for patients who received dapagliflozin than for those who received placebo, regardless of the presence or absence of diabetes comorbidity.
Although the trial had some generalizability limitations, it suggests clinically significant benefits from SGLT2 inhibition for patients with significant HFrEF, with or without diabetes.
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Heart Failure with Reduced Ejection Fraction: Treatment and Management
Faculty: Michael Cullen, MD
Manage acute and chronic heart failure with lifestyle, pharmacological, and device therapies.
Chronic Heart Failure Lifestyle Recommendations
Most lifestyle recommendations that have been applied to the HFpEF and the HFrEF population, suggest that patients should be encouraged to follow a sodium restriction: less than 2 to 3 grams per day, fluid restriction less than 2 liters per day particularly if you note hyponatremia in the labs that can suggest that they’re holding on to free water. Daily weight monitoring is very important. It helps patients get ahead of any potential exacerbations.
We encourage exercise 30 minutes a day, 5 days a week. Abstinence from alcohol. If that’s not possible, limited alcohol less than two drinks per day in men, less than one drink per day in women.
Treatment of sleep-disordered breathing. We’re understanding more and more of the overlap between sleep apnea and cardiac disease, heart failure, and arrhythmias. So, if you suspect sleep apnea, make sure it is evaluated and managed accordingly.
And then finally we have talked earlier about how heart failure is a progressive disease. It is never too early to have a discussion about the long-term goals of care.
When it comes to pharmacological therapy for HFrEF, you can break the medications into two big categories. On the one hand, we have drugs that reduce mortality. These include things like your ACE inhibitors and angiotensin receptor blockers, your beta-blockers, aldosterone antagonists, and hydralazine, and nitrates. And on the other hand, we have drugs that alleviate symptoms—your diuretics, digoxin, inotropes, or vasodilators.
The treatment of heart failure is going to depend on the patient’s stage.
So, in the stage A patients that are at risk for heart failure, we want to treat the risk factors, and this is what you do every day in primary care, right?
You treat hypertension. You tell people to stop smoking. You manage their lipids. You talk to them about exercise, talk to them about weight management, and maybe in certain high-risk patients, you might empirically treat them with an ACE or an ARB but I think that’s beyond the scope of anything you might see on internal medicine boards.
Stage B patients are an interesting group.
So remember these patients have structural heart disease with no symptoms of current or prior heart failure. I’m going to show you some interesting data on these stage B patients regarding their prognosis. This comes from a cohort of over 4,000 patients in the Framingham study that were stratified according to degrees of asymptomatic left ventricular dysfunction, which is ALVD. So in the blue line here, we have healthy controls. In the pink line, we have patients with mild asymptomatic left ventricular dysfunction, so an ejection fraction of 40% or greater but not normal who have no symptoms.
And then we have patients with moderate or severe asymptomatic left ventricular dysfunction so ejection fraction less than 40% but asymptomatic. And then here we have, in the green line, patients with systolic symptomatic heart failure.
And it’s clear that, yes, symptomatic patients do worse than asymptomatic patients, so your stage C patients are going to worse than your stage B patients. But progressive left ventricular dysfunction does portend a worse survival, even in asymptomatic patients.
ACE Inhibitors & ARB’s
If the patient has asymptomatic left ventricular dysfunction or other types of stage B heart failure, we should have them on an ACE or an ARB as a class I indication. Typically, we will start with the ACE inhibitor. The data is just a little bit better for ACE inhibitors, a little bit more robust. If they don’t tolerate the ACE inhibitor, then we can switch to an angiotensin receptor blocker.
These medications are okay to give as long as the creatinine is less than 2.5. You want to avoid giving the ACE and the ARB in combination. We also want to get these patients on a beta-blocker, class I indication. Now, remember that the combination of the ACE inhibitor and the beta-blocker or the ARB and the beta-blocker is better than either one alone. So you are better off using low doses of both of these medications than a higher dose of one med in isolation.
You want to avoid giving medications like diltiazem or verapamil, the non-dihydropyridine calcium channel blockers that have negative inotropic effects in patients with left ventricular dysfunction.
Here is how we give those medications for the ACE inhibitors and the angiotensin receptor blockers. We want to start the dose low, then titrate it up to the maximally tolerated dose or the goal dose over the course of several weeks typically changing the dose every 7 to 14 days. Same thing with the beta-blockers. We start the dose low. We titrate it up every 1 to 2 weeks to either the maximally tolerated dose or the goal doses that you see here.
Now, I want to mention a few caveats about beta-blockers. So, unlike the ACE inhibitors, the angiotensin receptor blockers, the beta-blockers, there’s no class effect.
Carvedilol, Metoprolol, and Succinate
The three beta-blockers that improve mortality in heart failure patients are carvedilol, metoprolol succinate, and bisoprolol.
Typically, in the U.S., it’s carvedilol or metoprolol succinate. So, no good data for metoprolol tartrate, atenolol or propranolol. If anyone understands why let me know. That being said, you should be using carvedilol or metoprolol succinate.
Now, a few differences between the two: carvedilol is more like labetalol. It has more alpha-blocking effects. It’s more vasoactive. It will lower the blood pressure more than metoprolol succinate. So, it’s preferred when blood pressure is not a limitation. However, if the patient is struggling with hypotension, we tend to use metoprolol succinate. Metoprolol succinate is also less likely to provoke bronchospasm. That being said, COPD is not a contraindication to using beta-blockers, particularly if the dose is started low and titrated up gradually.
Pharmacological Therapy In Each Stage
So that’s the stage B patients. The next to treatment of the stage B patients. So these patients have structural heart disease with symptoms. So these patients should all be getting an ACE inhibitor and beta-blocker, titrated to the maximally tolerated dose like we just talked about. Then, you’re going to consider adding a few different medications to improve their symptoms.
So, if they’re volume overloaded, add a diuretic. If they’re an African-American patient with class III to IV symptoms, they benefit from hydralazine and nitrates. This comes from the A-HeFT study which was published several years ago. Specifically, African-Americans tend to benefit from hydralazine and nitrates if they have stage C heart failure with ongoing functional limitations.
And then we’re going to think in the patients that have a significant reduction in their ejection fraction with class II to IV symptoms, potassium is not elevated, renal function is not overly impaired, those patients are going to benefit from an aldosterone antagonist like spironolactone or eplerenone.
Here is how we give some of those medications. So, for the aldosterone antagonist and the hydralazine and nitrates, the same principles that we saw for the ACE inhibitors, the angiotensin receptor blockers and the beta-blockers apply.
We start the dose low. We titrate it up every 1 to 2 weeks, increasing the dose to the maximally tolerated dose. With the aldosterone antagonist, in particular, it’s important to monitor electrolytes and potassium about 1 week after every dose adjustment. The diuretics are going to be titrated to the maximum necessary dose, unlike the other medications that improve mortality diuretics.
You’re going to use the lowest dose that you need to, to improve the patient’s symptoms. Bumetanide and torsemide tend to have better gut absorption, so I will often find those more effective in patients with right heart failure symptoms where they may have gut edema. So if you have a patient with right heart failure symptoms who’s struggling to diurese with Lasix. Sometimes they do well if you switch them over to torsemide. And then metolazone is sort of your backup medication when you’ve maxed out on the loop diuretic and you need something else to help get fluid off.
Digoxin is probably the oldest medication you’re going to learn about in this course. It still does have a role. It comes from the common Foxglove plant. It can be used for patients with heart failure with persistent symptoms despite medical therapy. I find it particularly effective if you need something to help with your rate control in atrial fibrillation. You want to make sure the level doesn’t get too high. Titrate the dose to a goal level of .5 to .9 nanogram per milliliter.
There are a few new medications on the block. We have the ARNI complex, sacubitril/valsartan, also known as Entresto. And we have ivabradine. Now both of these medications were FDA-approved in 2015. I think at this point it may be fair game to start to see these on boards. If not on boards, you’re certainly seeing these medications in your clinical practice.
So we’re going to talk a little bit here about sacubitril/valsartan, the ARNI complex, the brand name is Entresto. So, this is two medications in one. One component is valsartan which is the angiotensin receptor blocker that we all know and love and are familiar with, and then the other component is sacubitril.
Sacubitril / Valsartan (ARNi)
What is sacubitril? How does it work? Well, in order to understand sacubitril, we need to understand a little bit about the biochemistry of the natriuretic peptides. So we all produce this compound predominantly in our ventricles called proBNP. We produce it in response to ventricular stretch or increased load on the ventricles. And proBNP is cleaved into two compounds. We have NT-proBNP, which is an inert compound, and we have BNP, which is the active compound.
Now we can measure both of these in the blood and we use that as surrogates for heart failure or evaluation of patients with undiagnosed dyspnea like we talked about earlier. But from a mechanistic standpoint, BNP is where the rubber hits the road. So, BNP does all sorts of good things in patients with heart failure. It decreased neurohormonal activation, increases vasodilation, decrease fibrosis, decreases hypertrophy and promotes natriuresis.
And then we also have this compound called neprilysin, and neprilysin will degrade BNP into inactive metabolites and since deactivate BNP. So, sacubitril can come along and actually inhibit neprilysin. So that’s where we have angiotensin receptor blocker, neprilisyn-inhibitor; that’s where ARNI comes from. And by inhibiting neprilysin here, sacubitril is going to increase BNP levels and promote all of these good things that BNP does in heart failure patients. Now, this is important. If you’re measuring BNP levels in patients on Entrestor, you can’t do that because it’s going to be falsely elevated. That’s why we want to be measuring NTproBNP levels in those patients instead.
What’s the data behind this medication? Well, it comes from the PARADIGM-HF study which was a large randomized control trial of enalapril versus sacubitril/valsartan in patients with HFrEF, heart failure with reduced ejection fraction. And in the patients who got sacubitril/valsartan, all sorts of good things happened. So they had decreased rates of heart failure hospitalization, decreased cardiovascular mortality, you see the survival code for the primary outcome here, and decreased all-cause mortality overall.
This data led to a guideline update in 2017. The ARNI compound now has a class I recommendation for patients with chronic symptomatic HFrEF who have demonstrated the ability to tolerate an ACE or an ARB, and the recommendation is that replacement of an ACE inhibitor or angiotensin receptor blocker with an ARNI is recommended to further reduce morbidity and mortality.
Barriers to Medication
There’s lots of barriers to using this medication; particularly cost and prior authorization and all that stuff which we don’t need to get into here. But, from the guideline standpoint, from the purposes of your boards, this is something that you should understand.
Now, a few caveats about using these medications. We want to avoid using them with an ACE inhibitor because the combination of the ACE, the ARB, and sacubitril can really increase the risk of angioedema. Furthermore, we want to avoid if there is any history of angioedema. We could potentially provoke it with these medications even if they’ve had angioedema due to an ACE inhibitor, you can provoke that angioedema with the sacubitril and valsartan combination.
Ivabradine inhibits the sinoatrial node and significantly reduces the heart rate and it has a class IIa recommendation for heart failure patients with symptomatic HFrEF and a heart rate over 70 despite maximum beta-blockade.
That’s a pretty select indication. I can count on one hand, the number of patients in my practice that I’ve given ivabradine to. It actually worked. Lowered his heart rate quite a bit. He’s doing well, but it’s a pretty specific indication and you’re probably not going to see it a whole lot in your practice. I just want to make you aware.
Stage D Heart Failure Treatment
The final category of heart failure therapy is those with stage D heart failure treatment. These patients often require treatment with heart transplants, your mechanical circulatory support. That sort of goes beyond the scope of what we’re talking about here. I’m going to get into that in detail.
When to Hospitalize
A patient with heart failure shows up in your clinic and you get the sense that they’re not doing well. When should you put this patient in the hospital? Well, you want to look for volume overload, one, poor cardiac output, two. How does that manifest?
Well, if the patient has respiratory compromise, unstable ischemic symptoms, persistent resting dyspnea, symptomatic hypotension, altered mentation or worsening renal function. All of these would be reasonable indications to put the patient in the hospital.
Acute Heart Failure Management
If you put a patient in the hospital, then what do you do with them when they’re there? Well, I’d encourage you, when you see these patients in the hospital, you need to ask yourself two questions.
First of all, is the patient congested? Do they have elevated neck veins? Do they have rales in their lungs? Do you hear an S3 gallop? Do they have orthopnea or edema?
Secondly, are they pumping blood forward? How are they perfusing? Is their pulse pressure low, which is a surrogate for low stroke volume. Are their extremities cool, which means they’re not pumping a lot of blood flow. Are they hypotensive?
Again, reflective of poor cardiac output. And then based on the answers to these two questions, you can put them into one or four boxes. So if they’re not congested and they’re perfusing normal, they’re warm and dry. If they’re congested but they’re perfusing normally, they’re warm and wet. Okay, if they’re not congested, the perfusion is low, they’re cool and dry. And if they’re congested and they’re not perfusing well, they’re cool and wet.
If the patient is warm and dry, that’s great. Get them out of the hospital or tell the ED why you were admitting this patient. That’s the point you want to get them to. If they’re warm and wet, they’re congested but they’re perfusing adequately, get the fluid off. Diurese them. If they’re cool and dry, so volume overload is not a problem. It’s forward flow that’s a problem. These are the patients that need ionotropes, potentially mechanical circulatory support. And then if they’re cool and wet, then we diurese them and sometimes just diuresis itself can help improve forward flow. These patients may also benefit from inotropes or vasodilators like nitroprusside.
So hopefully this gives you a reasonable schematic to think about when you’re taking care of these heart failure patients in the hospital. In terms of what to do with their medications, diuretics are going to be important. When you’re initially diuresing the patient, if that’s indicated, you start the IV diuretic two times the total daily oral dose.
So, if the patient is on 20 BID Lasix as an outpatient, that’s 40 milligrams total. Start with 80 IV and go from there. In terms of the ACEs or the ARBs, you want to continue them unless you see a really big increase in the creatinine; I would say 2.5 or greater. Or, if they’re potassium’s out of whack, if they’re not on an ACE or an ARB, start it within 24 hours of admission. The beta-blockers, you want to hold the beta-blocker or decrease the beta-blocker if they’re struggling, if they’re hypotensive, if they’re severely volume overloaded because the beta-blocker in that acute situation can limit forward flow.
If the patient is not on a beta-blocker, you want to try and get them on a beta-blocker before they leave the hospital, but you don’t want to start the beta-blocker acutely. Dry the patient out, stabilize them first, then put them on a beta-blocker, because if you start the beta-blocker in the acute situation, you could make things a lot worse because acutely beta-blockers are going to decrease cardiac output.
Device Therapy for Heart Failure
When you think about device therapy for heart failure, you want to be asking yourself two questions. First of all, who needs a defibrillator? Secondly, who needs a biventricular pacemaker where we pace the left and the right ventricle simultaneously, also known as cardiac resynchronization therapy. So who needs a defibrillator?
Two groups of patients. One, those with a prior cardiac arrest. So if the patient has died once, they are at risk of dying again. Therefore, they merit consideration of a defibrillator. The perhaps more challenging question is, who needs a defibrillator for primary prevention? Well, these are patients with functional class II to III symptoms who are already on good medical therapy who have a reasonable life expectancy and persistently low ejection fraction less than 35% and are at least 40 days after an infarct.
We don’t want to be putting defibrillators in you right away after an infarct because left ventricular function can also recover.
If you understand who needs a defibrillator, then you have a good understanding of who needs biventricular pacing because the same criteria apply with the additional criteria that patients who have ventricular desynchrony characterized by either a left bundle branch block or a wide QRS on your ECG may benefit from cardiac resynchronization to eliminate the desynchrony in the left ventricular where the septum and the lateral wall contract at different times; thus potentially limiting forward flow.
Now other indications exist for these devices, but I think these are the important ones to know for your practice and your boards. All right, well, we’ve covered a lot of ground. We’ve talked about the definitions and scope of heart failure. We’ve talked about the diagnostic evaluation and then we’ve talked about management of chronic heart failure, acute heart failure, and device-based management of heart failure.