Key Steps to Optimizing GDMT in Heart Failure

This transcript has been edited for clarity.

Hello. My name is Biykem Bozkurt. I'm a heart failure cardiologist, professor of medicine, senior dean of faculty, and director of Winters Center for Heart Failure Research at Baylor College of Medicine. Today, we're discussing tips for optimizing guideline-directed medical therapy (GDMT) in heart failure.

I want to talk about optimization strategies according to stages of heart failure in clear steps according to ejection fraction classification. In the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure, we have specific recommendations according to stages of heart failure. We revised the heart failure stage terminologies for these to be better understood by our patients and by nonspecialists.

The first stage in heart failure is patients with risk factors, such as diabetes, hypertension, coronary artery disease, and obesity, but without symptoms or signs or functional or structural cardiac abnormalities. We define this as stage A or at risk for heart failure.

The second stage is patients without symptoms or signs but with structural, functional, or biomarker abnormalities. This stage is called pre–heart failure or stage B. Patients with current or prior symptoms of heart failure are called stage C or symptomatic heart failure. Patients with advanced symptoms or signs with high-risk features, such as repeated hospitalizations or intolerance to GDMT, is defined as advanced heart failure or stage D.

We have specific recommendations for each stage. We also have a classification according to ejection fraction because of the existing evidence for treatment according to different ejection fraction classifications. Let's go over these ejection fraction classifications.

Patients with ejection fraction of 40% or less are classified as having heart failure with reduced ejection fraction, with ejection fraction between 41% and 49% as having mildly reduced ejection fraction, and with ejection fraction 50% or more as having preserved ejection fraction.

We also have a new category in the guidelines defined as heart failure with improved ejection fraction. These are patients with history of ejection fraction of 40% or less whose ejection fraction may have improved to more than 40% with treatment. These individuals need to be continued on GDMT despite resolution of symptoms or normalization of ejection fraction.

Let's go over the steps of GDMT in patients with symptomatic heart failure with reduced ejection fraction. The first step is initiation of quadruple therapy. This includes sodium-glucose cotransporter 2 (SGLT2) inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and renin-angiotensin-aldosterone system (RAAS) inhibition, with either angiotensin receptor-neprilysin inhibitors (ARNIs) in patients with New York Heart Association (NYHA) class II-III or angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with NYHA class II-IV heart failure.

These medications have been demonstrated to result in significant improvements in cardiovascular death and heart failure hospitalization as early as 30 days after initiation. Therefore, timely initiation is critical to prevent adverse outcomes.

Newer agents, such as ARNI and SGLT2 inhibitors, have beneficial effects also in the kidney. They slow the decline in estimated glomerular filtration rate and they also improve quality of life. They are effective not only in cardiovascular disease but also in renal outcomes and improving patient-reported outcomes. These medications are safe when compared with comparator or placebo and can be safely initiated predischarge.

Quadruple Therapy Initiation

In the guidelines, we specify that all four classes can be initiated simultaneously at low doses, or alternatively, these medications may be started sequentially. The sequence should be guided by clinical factors, not necessarily according to the historical way that the trials were conducted.

These medications can be initiated simultaneously without waiting to achieve optimal dose of the prior medication. In clinical practice, sequence can be individualized according to patient etiologies.

For example, in the outpatient setting, for a patient with active ischemia or tachycardia, beta-blockers may be prioritized. For a patient with advanced chronic kidney disease, SGLT2 inhibitors may be prioritized followed by ARNI. For a patient with significant congestion and NYHA class III symptoms with recurrent hospitalizations who has been treated with diuretics, SGLT2 inhibitors, ARNIs, and MRAs may be prioritized and then followed with beta-blockade.

Step two is for the doses of the four classes of medication to be increased to target doses as tolerated. We have evidence of better outcomes, especially with beta-blocker and ACE inhibitor dose optimization. If we examine the number of dose titrations required for each class, it should be noted that SGLT2 inhibition is only one standard dose.

An MRA may require only one or two steps for optimization of doses. ACE inhibitors and beta-blockers may require two to three steps. Regardless, the maximum tolerated dose should be achieved in a few encounters ­— in two to three encounters — and not delayed beyond 4-6 weeks.

Please also keep in mind that the new agents, such as SGLT2 inhibitors and ARNI, have a safe profile on the kidney and potassium levels. They facilitate and enable initiation and continuation of other agents, such as MRAs.

Steps three and four are to optimize therapy further if patients remain symptomatic. Hydralazine and nitrates are indicated in patients who identify as African American or Black. Device therapies such as implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) should be considered for indicated patients. An ICD is indicated in patients with reduced ejection fraction of 35% or less and CRT in patients with symptomatic heart failure with ejection fraction of 35% or less and wide QRS.

Step five is to consider additional therapies, such as ivabradine, in symptomatic patients with heart failure with reduced ejection fraction and a heart rate ≥ 70 beats/min at rest despite maximum dose of beta-blockers. Vericiguat can be considered in symptomatic patients with recent heart failure hospitalizations or elevated natriuretic peptide levels.

Digoxin can be considered in symptomatic patients with heart failure, polyunsaturated fatty acid supplementation in patients with heart failure with NYHA class II-IV heart failure symptoms, and potassium binders can be considered in patients with hyperkalemia while taking RAAS inhibitors.

In addition, in the guidelines, we have specified that surgical revascularization is indicated among select patients with suitable coronary anatomy and ischemic cardiomyopathy. Transcatheter edge-to-edge mitral valve repair can be considered among patients with secondary mitral regurgitation (MR), suitable anatomy, ejection fraction between 20% and 50%, with left ventricular end-systolic dimension ≤ 70 mm and pulmonary artery systolic pressure is ≤ 70 mm Hg after optimization of GDMT. It's critical to remember that GDMT should be optimized before consideration of intervention for secondary MR.

In the guidelines, we also have specific recommendations for patients with heart failure with mildly reduced ejection fraction as well as preserved ejection fraction. We have evidence from two large-scale trials that SGLT2 inhibitors are effective in reducing cardiovascular mortality and heart failure hospitalizations in all patients with ejection fraction 40% or more. These include patients with mildly reduced ejection fraction and preserved ejection fraction. Thus, SGLT2 inhibitors have a higher level of recommendation for treatment of patients with mildly reduced ejection fraction or preserved ejection fraction than do other medications.

After SGLT2 inhibitors, ACE inhibitors, ARBs, beta-blockers, and MRAs can be considered for patients in mildly reduced ejection fraction. ARNIs, ARBs, or MRAs can be considered in patients with heart failure with preserved ejection fraction. Please note that beta-blockers are not indicated in patients with heart failure with preserved ejection fraction. Though they are commonly used for other indications in patients with heart failure with preserved ejection fraction, such as for ischemic heart disease or for atrial fibrillation rate control, we do not have any evidence of benefit with beta-blockers in patients with heart failure with preserved ejection fraction.

Treating Comorbidities in HF

The next step is treatment of comorbidities. We have specific recommendations to screen for iron deficiency in all patients with heart failure and treatment of iron deficiency with intravenous iron to improve symptoms, functional capacity, and quality of life.

Hypertension should be optimally treated according to guidelines. We recommend SGLT2 inhibition for management of hyperglycemia in patients with diabetes and heart failure regardless of ejection fraction. This is a separate recommendation than the indication of SGLT2 inhibitors for treatment of heart failure with reduced ejection fraction.

For treatment of hyperglycemia in patients with heart failure and diabetes, the SGLT2 inhibitors are recommended as a class I indication. We also have recommendations for consideration of atrial fibrillation ablation in patients with atrial fibrillation and symptoms attributable to atrial fibrillation.

Heart failure outcomes, unfortunately, are very similar to that of cancer. There is an urgency not to delay the therapies in this deadly disease. For this reason, I use the analogy of calling the initiation of quadruple therapy in patients with heart failure with reduced ejection fraction the induction therapy.

I consider additional therapies as consolidation therapy to alert the clinicians of the importance of timely initiation and optimization of therapies in heart failure. Keep in mind that we have strong evidence that implementation can be enhanced when therapies are initiated before discharge in patients hospitalized for heart failure.

Initiation pre-discharge and optimization within 2 weeks post discharge is effective and safe. There is also evidence that hybrid models involving uptitration with virtual telehealth or multidisciplinary care coordination approaches are effective. Electronic health records can also help optimize GDMT implementation at the network level.

With such coordinated efforts, we hope that these disease-modifying therapies will effectively be implemented and change the trajectory of this deadly disease that is affecting more than 6 million adults in the United States. Thank you for your attention.

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